KR0177840B1 - Octahydronaphthalene oxime derivative for inhibiting cholesterol biosynthesis and its preparation - Google Patents

Abstract

A compound of formula (I) having the ability to inhibit cholesterol biosynthesis and therefore useful for the treatment and prevention of diseases relating to high blood pressure cholesterol levels.

[Wherein R is hydrogen, methyl or hydroxy; X is an alkyl, alkenyl, cycloalkyl, aryl, aralkyl or heterocyclic group; A is a single bond or an alkylene, alkenylene, alkynylene or alkadienylene group; Y is hydrogen, aryl, cycloalkyl or a heterocyclic group. ]

Description

Octahydronaphthalene oxime derivative for inhibiting cholesterol biosynthesis and its preparation

The present invention relates to a series of novel octahydronaphthalene oxime derivatives having the ability to inhibit the biosynthesis of cholesterol. The present invention also provides methods for the preparation of these compounds as well as compositions and methods of using these compounds.

Several compounds are known which may generally be described as 7- [substituted 1, 2, 3, 5, 6, 7, 8, 8a-octahydro 1-naphthyl] -3,5-dihydroxyheptanoate. It is considered that the closest of them is the harmony of the following formula (A).

[Wherein A, R, X and Y are essentially the same as defined hereinafter for the compounds of the invention. Among others, these compounds are disclosed in European Patent Publication No. 314 435 and also described in more detail here as development and precursors for this type of compound. Such a compound of formula (A) is considered to be the compound closest to the compound of the present invention. Since the compounds of the prior art have the ability to inhibit the biosynthesis of cholesterol as the compounds of the present invention, they can be used for the prevention and treatment of various diseases caused by hypercholesterolemia such as atherosclerosis and various heart diseases.

A class of compounds that are somewhat similar to the compounds of the present invention are those described in Japanese Patent Application Laid-Open, Digestion No. 60-123445 (European Patent Publication No. 142 146) and Journal of medicinal Chemistry 32, 197 (1989). . They can be represented by the following formulas (B) and (C):

[Wherein E represents a group of the formula -CH ₂ CH _2- , -CH = CH-or-(CH ₂ ) _3- ; A ¹ represents a hydrogen atom or a lower alkyl group; A ² represents a lower alkyl group; A ³ represents a hydrogen atom or a methyl group; A ⁴ , A ⁵ and A ⁶ are the same as or different from each other, and each represent a hydrogen atom, a halogen atom, a lower alkyl group or an unsubstituted phenyl group.]

Also known are compounds having a hydroxy group in place of the 5-oxo group and corresponding to the above compounds of formulas (B) and (C). They are known to have the ability to inhibit biosynthesis of cholesterol consistently greater than the corresponding 5-oxo compounds.

It was surprisingly found that the 5-oxo compound corresponding to the 5-hydroxy compound of formula (A) had another ability to inhibit cholesterol biosynthesis significantly greater than the 5-hydroxy compound of formula (A).

The present invention therefore provides novel compounds of formula 1, pharmaceutically acceptable salts and esters thereof:

Wherein R represents a hydrogen atom, a methyl group or a hydroxy group; X is carbon number substituted by one or more alkyl groups of 1 to 10 carbon atoms, alkenyl groups of 3 to 10 carbon atoms, cycloalkyl groups of 3 to 10 carbon atoms, aryl groups of 6 to 10 carbon atoms, and carbocyclic aryl groups having 6 to 10 carbon atoms. An aralkyl group having 1 to 6 alkyl groups or a heterocyclic group having 5 to 6 ring atoms having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, wherein the alkyl and alkenyl groups are unsubstituted or , At least one substituent selected from the group consisting of substituents A defined below, wherein the cycloalkyl, aryl, aralkyl and heterocyclic groups are unsubstituted or have at least one substituent selected from the group consisting of substituents B defined below; A is a single bond, an alkylene group having 1 to 10 carbon atoms, an alkenylene having 3 to 10 carbon atoms, an alkynylene group having 3 to 10 carbon atoms, or an alkadieneylene group having 5 to 10 carbon atoms, and the alkylene and alke The nylene, alkynylene and alkadienylene groups are unsubstituted or have one or more substituents selected from the group consisting of substituents C as defined below;

Y is a heterocyclic group having 5 or 6 ring atoms having 1 to 3 heteroatoms selected from the group consisting of a hydrogen atom, an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, nitrogen, oxygen and a sulfur hetero atom, or A heterocyclic group having 5 to 6 ring atoms bonded to a benzene ring having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur heteroatoms, wherein the aryl, cycloalkyl and heterocyclic groups are unsubstituted or Has at least one substituent selected from substituents D defined;

[Substituent A]

Halogen atom, hydroxy group, alkoxy group having 1 to 4 carbon atoms, aliphatic carboxylic acyloxy group having 2 to 5 carbon atoms, amino group, carboxyl group and protected carboxyl group;

[Substituent B]

Halogen atom, hydroxy group, alkoxy group having 1 to 4 carbon atoms, aliphatic carboxylic acyloxy group having 2 to 5 carbon atoms, amino group, carboxyl group and protected carboxyl group, alkyl group having 1 to 5 carbon atoms and haloalkyl group having 1 to 5 carbon atoms;

[Substituent C]

Halogen atom, hydroxy group, alkoxy group of 1 to 4 carbon atoms, aryloxy group of 6 to 14 carbon atoms, aralkyloxy group, aliphatic carboxylic acyloxy group of 2 to 5 carbon atoms, aromatic carboxylic acyl of 7 to 15 carbon atoms An oxy group, an amino group, a C1-C4 alkylamino group, each alkyl group has a C1-C4 dialkylamino group, a C6-C14 arylamino group, each aryl group has a C6-C14 diarylamino group, aralkylamino group , Dialkylalkyl group, aliphatic carboxylic acylamino group having 2 to 5 carbon atoms, aromatic carboxylic acylamino group having 7 to 15 carbon atoms, carboxyl group and protected carboxyl group, wherein the aryloxy, aralkyloxy, aromatic carboxylic group The aryl groups of acyloxy, arylamino, diarylamino, aralkylamino, diaralkylamino and aromatic carboxylic acylamino groups are unsubstituted or defined below. Has one or more substituents selected from the group consisting of substituents E, wherein the aralkyl moiety for each of the aralkyloxy, aralkylamino and diaralkylamino groups has 1 to 6 carbon atoms substituted with one or more aryl groups having 6 to 10 carbon atoms. 6 is an alkyl group:

[Substituent D]

Halogen atom, hydroxy group, alkoxy group of 1 to 4 carbon atoms, aryloxy group of 6 to 14 carbon atoms, aralkyloxy group, aliphatic carboxylic acyloxy group of 2 to 5 carbon atoms, aromatic carboxylic acyl of 7 to 15 carbon atoms An oxy group, a mercapto group, an alkylthio group having 1 to 4 carbon atoms, an arylthio group having 6 to 14 carbon atoms, an aralkylthio group, an amino group, an alkylamino group having 1 to 4 carbon atoms, and each alkyl group having 1 to 4 carbon atoms Dialkylamino group, C6-C14 arylamino group, Each aryl group C6-C14 Diarylamino group, Aralkylamino group, Diaralkylamino group, C2-C5 aliphatic carboxylic acylamino group, C7-C14 In the group consisting of an aromatic carboxylic acylamino group of 15, a nitro group, a cyano group, a carboxyl group, a protected carboxyl group, an alkyl group having 1 to 5 carbon atoms and a substituent having 1 to 5 carbon atoms and defined below An alkyl group substituted with one or more substituents selected, wherein said aryloxy, aralkyloxy, aromatic carboxylic acyloxy, arylthio, aralkylthio, arylamino, diarylamino, aralkylamino, diaralkylamino and The aryl group of the aromatic carboxylic acylamino group has one or more substituents selected from the group consisting of substituents E unsubstituted or defined herein, wherein each of the aralkyloxy, aralkylthio, aralkylamino and diaralkylamino groups An aralkyl moiety is an alkyl group having 1 to 6 carbon atoms substituted by one or more aryl groups having 6 to 10 carbon atoms;

[Substituent E]

An alkyl group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a carboxyl group, a protected carboxyl group and an amino group;

[Substituent F]

Halogen atom, a hydroxyl group, and the C2-C5 aliphatic carboxylic acyloxy group.

The invention also provides a pharmaceutical composition consisting of an agent for inhibiting cholesterol biosynthesis selected from the group consisting of a compound of Formula 1 as defined above and a pharmaceutically acceptable salt and ester thereof, in admixture with a pharmaceutically acceptable carrier or diluent. It is.

The invention also comprises administering to a mammal suffering from a disease caused by blood cholesterol imbalance an effective amount of a cholesterol biosynthesis inhibitor selected from the group consisting of a compound of Formula 1 as defined above and a pharmaceutically acceptable salt and ester thereof It provides a method for treating a mammal.

The invention also provides a process for the preparation of the compounds of the invention, which will be described in more detail below.

In Formula 1, when X represents an alkyl group, it may be a linear or branched alkyl group having 1 to 10 carbon atoms, preferably 1 to 7 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, S − Butyl, isobutyl, t-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, 1, 1-dimethylpropyl, neopentyl, 1, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1- Methylpentyl, 2-methylpentyl, 1, 1-dimethylbutyl, 1, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1-methyl-1 -ethylpropyl, heptyl, 1 -methyl-1 -ethyl Butyl, 2-methyl-2-ethylbutyl, octyl, 1-methylheptyl, 2-ethylhexyl, 1, 1, 3, 3-tetramethylbutyl, nonyl, decyl or 3, 7-dimethyloctyl group. Such groups may be unsubstituted or substituted with one or more substituents selected from the group consisting of substituents A defined above and illustrated below. There is no particular limitation on the number of substituents other than those imposed by the number of substitutable positions (eg, 3 in methyl, 5 in ethyl, etc.) or steric hindrance. However, generally 1-4, more preferably 1-3 substituents are preferable. The same applies to other substituents which do not mention the specific number of substituents. Specific examples of preferred substituted alkyl groups include trichloromethyl, trifluoromethyl, chloromethyl, fluoromethyl, bromomethyl, iodomethyl, hydroxymethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, Methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, aminomethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, 2, 2, 2-trichloroethyl, 2 , 2, 2-trifluoroethyl, 1-chloroethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-carboxyethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-butoxyethyl , 1-aminoethyl, 2-aminoethyl, 2-acetoxyethyl, 2-propionyloxyethyl, 2-butyryl Cyethyl, 2-pivaloyloxyethyl, 3-chloropropyl, 1-fluoropropyl, 3-fluoropropyl, 3-bromopropyl, 3-iodopropyl, 1, 1-difluoropropyl, 3 -Hydroxypropyl, 3-carboxypropyl, 3-methoxycarbonylpropyl, 3-ethoxycarbonylpropyl, 1-ethoxycarbonyl-1-methylethyl, 1-amino-3-methoxycarbonylpropyl, 1-Fluoro-1-methylpropyl, 1-ethyl-1-fluoropropyl, 1-amino-2-methylpropyl, 4-hydroxybutyl, 3-acetoxy-1,1-dimethylpropyl, 4-acetyl Methoxy-1-methylbutyl, 3-hydroxy-1,1-dimethylpropyl, 4-ethoxycarbonyl-1-methylbutyl, 1-chloro-1-methylpropyl and 4-hydroxy-1,1-dimethyl It contains a butyl group.

When X represents an alkenyl group, it may be a linear or branched alkenyl group having 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms. For example 1-propenyl, 2-propenyl, 1-methylvinyl, 2-butenyl, 3-butenyl, 1-methyl-1 propenyl, 2-methyl-2-propenyl, 3-methyl- 2-butenyl, 2-pentenyl, 3-pentenyl, 4-hexenyl, 1-hexenyl, 5-heptenyl, 2-octenyl, 4-octenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 3-desenyl or 5-desenyl groups. Such groups may be unsubstituted or substituted with one or more substituents selected from the group consisting of substituents A, defined above and illustrated below.

When X represents a cycloalkyl group, it may be cycloalkyl having 3 to 10 carbon atoms, preferably cycloalkyl having 3 to 7 carbon atoms, and may be a monocyclic or polycyclic group which is for example bicyclic and is a polycyclic group. , A ring hydrocarbon group bonded or crosslinked. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bornyl, norbornyl and adamantyl groups. Of these, monocyclic groups having 3 to 7 ring carbon atoms are particularly preferred, and cyclopropyl, cyclopentyl and cyclohexyl groups are most particularly preferred.

When X represents an aryl group, it is a carbocyclic aromatic group and may have 6 to 10 ring carbon atoms, more preferably 6 or 10 ring carbon atoms. Examples thereof include phenyl, 1-naphthyl and 2-naphthyl groups, preferably phenyl groups. Such groups may be unsubstituted or substituted with at least one substituent selected from the group consisting of substituents B defined above and illustrated below. Preferred specific examples of substituted aryl groups are 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-trifluoromethylphenyl, 3 -Trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyhenyl, 2 Acetoxyphenyl, 3-acetoxyphenyl, 4-acetoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-propylphenyl, 3 -Propylphenyl, 4-propylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2, 6-dimethylphenyl, 3, 4-dimethylphenyl, 3, 5-dimethylphenyl and 2, 5-dimethylphenyl group.

When X represents an aralkyl group, it is an alkyl group having 1 to 6 carbon atoms substituted with at least one aryl group as defined above. It preferably has a total of 7 to 12 carbon atoms, more preferably 7 to 9 carbon atoms; The alkyl moiety preferably has 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, most preferably 1 or 2 carbon atoms; The aryl moiety preferably has 6 to 10 carbon atoms, more preferably 6 or 10 carbon atoms, most preferably a phenyl group. It may have one or more, preferably one to three aryl groups, most preferably one aryl group. Examples of such groups include benzyl, benzhydryl, trityl, α-methylbenzyl, α-naphthyl methyl, β-naphthylmethyl, phenethyl, 3-phenylpropyl, 1, 1-dimethylbenzyl, 4-phenylphenyl , 1-methyl-3-phenylpropyl, 5-phenylpentyl and 6-phenylhexyl groups. Such groups may be unsubstituted or substituted with at least one or more substituents selected from the group consisting of substituents B defined above and illustrated below. Specific examples of preferred substituted aryl groups include those unsubstituted groups in which the phenyl group is replaced by any of the substituted aryl groups exemplified above with respect to the substituted aryl group which may be represented by X.

When X represents a heterocyclic group, it contains 5 or 6 ring atoms, of which 1-3 are oxygen atoms and / or sulfur atoms and / or nitrogen atoms. If the group contains one or two heteroatoms, these or these may be freely selected from nitrogen, oxygen and sulfur hetero-atoms. If the group contains three hetero atoms, it is preferred that one, two or three of them must be nitrogen atoms, and correspondingly two, one or zero atoms must be oxygen or sulfur atoms. It may be a fully unsaturated heterocyclic group, and examples of such groups include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 1-pyrrolyl, 2- Pyrrolyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 5-pyrimidinyl, 2-pyranyl, 4-pyranyl, 3-isoxazolyl, 5-isoxazolyl, 2-oxa Zolyl and 5-oxazolyl groups. Alternatively fully or partially saturated groups such as 2-tetrahydrofuryl, 3-tetrahydrofuryl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 1-pyrrolidinyl, 3-py Lolidinyl, 2-piperazil, piperidino, 2-piperidyl, morpholino, 3-morpholinyl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 1, 4-dioxane-2 -Day, 1, 3-Dioxane-4-Day or 1, 3-Dioxane-5-Diary. Among these, 5- and 6-membered unsaturated heterocyclic groups containing 1 to 3 oxygen atoms and / or sulfur atoms and / or nitrogen atoms are preferable.

When X represents an alkyl group or an alkenyl group, such groups may be substituted or unsubstituted, and if substituted, the substituents are selected from the group consisting of substituents A as defined above. In principle, the number of substituents on the alkyl or alkenyl group represented by X is not limited except the number of substitutable positions and possibly steric hindrance. In general, however, there should preferably be 1 to 4, more preferably 1 or 2 substituents. If two or more such substituents are present, they may be the same or different from one another, and examples thereof include the following groups and atoms:

Halogen atoms such as chlorine, bromine, iodine and fluorine atoms; Hydroxyl group; Alkoxy groups having 1 to 4 carbon atoms such as methoxy and ethoxy groups; C ₂ -C ₅ aliphatic carboxylic acyloxy groups such as acetoxy, propionyloxy, butyryloxy, valeryloxy, isovaleryloxy and pivaloyloxy groups, especially C ₂ -C ₅ alkanoyloxy groups; Amino group; Carboxyl group; And protected groups are preferably protected carboxy groups as defined below. Protecting groups for carboxyl groups are known in the art and there will be no difficulty in determining which groups can be used by those skilled in the art. For illustration purposes only, there may be mentioned, for example, lower alkyl groups (e.g., 1 to 4 carbon atoms) to form protected groups such as methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl groups; An aralkyl group (preferably as a group which may be represented by X) for forming an aralkyloxycarbonyl group such as benzyloxycarbonyl, diphenylmethoxycarbonyl, 4-nitrobenzyloxycarbonyl and 2-nitrobenzyloxycarbonyl group As defined above); Lower alkenyl and haloalkenyl groups (e.g., 1 to 4 carbon atoms) for forming alkenyloxycarbonyl or haloalkenyloxycarbonyl groups such as allyloxycarbonyl and 2-chloroallyloxy carbonyl groups; Lower haloalkyl groups (eg 1 to 4 carbon atoms) for forming haloalkoxycarbonyl groups such as 2, 2, 2-trichloroethoxycarbonyl and 2, 2, 2-tribromoethoxycarbonyl group; And a substituent for forming a silylalkoxy carbonyl group such as 2-(trimethylsilyl) ethoxycarbonyl group, preferably a tri (substituted) alkyl group having 1 to 4 carbon atoms and / or a phenyl group and having 1 to 4 carbon atoms in the alkyl group. And silylalkyl groups. As ester groups for forming esters of the compounds of the present invention, other protecting groups which may be used are described below. For example, when referring to a protected carboxy group in connection with substituents A, B, C, D and E, all such protecting groups are included.

Among these substituents, most preferred are a halogen atom, a hydroxyl group, an aliphatic carboxylic acyloxy group having 2 to 5 carbon atoms, a carboxyl group, and a protected carboxyl group, of which the most preferred are halogen atoms and carboxyl groups.

When X represents a cycloalkyl group, an aryl group, an aralkyl group or a heterocyclic group, such a group may be substituted or unsubstituted and if substituted the substituent is selected from the group consisting of the substituents B as defined above. The number of substituents on the cycloalkyl, aryl, aralkyl or heterocyclic groups represented by X is not inherently limited, except for the number of substitutable positions and possibly steric hindrance. In general, however, these substituents should preferably be 1 to 4, more preferably 1 or 2. When two or more substituents are present, they may be the same or different from one another, and examples thereof include the following groups and atoms:

Halogen atoms such as chlorine, bromine, iodine and fluorine atoms; Hydroxyl group; Alkoxy groups having 1 to 4 carbon atoms such as methoxy and ethoxy groups; C ₂ -C ₅ aliphatic carboxylic acyloxy groups such as acetoxy, propionyloxy, butyryloxy, valeryloxy, isovaleryloxy and pivaloyloxy groups, especially C ₂ -C ₅ alkanoyloxy groups; Amino group; Carboxyl group; Methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, diphenylmethoxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, allyloxycarbonyl, Preferred substituents, such as 2 -chloroallyloxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, 2, 2, 2-tribromoethoxycarbonyl and 2-(trimethylsilyl) ethyloxycarbonyl groups Protected carboxyl groups having a protecting group as defined above for the protected group of A; C ₁ to C ₅ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl and pentyl groups; And halogen-substituted C ₁ to C ₅ alkyl groups such as trifluoromethyl groups.

Among these substituents, halogen atoms, hydroxy groups, alkoxy groups having 1 to 4 carbon atoms, C ₂ to C ₅ aliphatic carboxylic acyloxy groups, C ₁ to C ₅ alkyl groups and halogen-substituted C ₁ to C ₅ alkyl groups are most preferred. Of these, halogen atoms and halogen-substituted C ₁ to C ₅ alkyl groups are most preferred.

When A represents a divalent saturated acyclic hydrocarbon group, this may be an alkylene group having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms. The group may be a straight or branched group, the two free atoms may be on the same carbon atom (in this case the group is sometimes known as an alkylidene group), or may be on a different carbon atom. Examples of such groups are methylene, ethylidene, ethylene, 1-methylethylene, trimethylene, 1, 2-dimethylethylene, 1-ethylethylene, 1-methyltrimethylene, 2-methyltrimethylene, tetramethylene, 1-propyl Ethylene, 1-ethyl-2-methylethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 1,3-dimethyltrimethylene, 1-methyltetramethylene, 2-methyltetramethylene, pentamethylene, 1-butylethylene 1-methyl-2-propylethylene, 1,2-diethylethylene, 1-methyl-1-propyl-ethylene, 2-propyltriethylene, 1-ethyl-3 methyltrimethylene, 1-ethyltetramethylene, 2-ethyltetramethylene, 1,3-dimethyltetramethylene, 1-methylpentamethylene, 2-methylpentamethylene, 3-methylpentamethylene, hexamethylene, 1-pentylethylene, 1-butyl-2-methylethylene, 1 -Ethyl-2-propylethylene, 1-butyltrimethylene, 2-butyltrimethylene, 1,3-diethyl Methylene, 1-methyl-3-propyltrimethylene, 1-propyltetramethylene, 2-propyltetramethylene, 1-ethyl-4-methyltetramethylene, 3-ethyl-1-methyltetramethylene, 1-ethylpentamethylene, 3-Ethylpentamethylene, 1,3-dimethylpentamethylene, 1-methylhexamethylene, 3-methylhexamethylene, heptamethylene, 1-hexylethylene, 1-methyl-2-pentylethylene, 1-butyl-2- 2-ethyl Ethylene, 1, 2-dipropylethylene, 1-pentyltrimethylene, 2-pentyltrimethylene, 1-butyl-3 methyltrimethylene, 1-butyl-2-methyltrimethylene, 1-ethyl-3 Propyltrimethylene, 1, 2-Dimethyl-3-propyltrimethylene, 1-butyltetramethylene, 1-methyl-4-propyltetramethylene, 1-propylpentamethylene, 3-propylpentamethylene, 2-ethyl-4 Methylpentamethylene, 1-ethylhexamethylene, 3-ethylhexamethylene, 1,3-dimethylhexamethylene, 1-methylheptamethylene, 4-methylheptamethylene, octamethylene, and 2, 6- dimethyloctamethylene are mentioned.

When A represents a divalent unsaturated acyclic hydrocarbon group, this may be an alkenylene group having 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms, and most preferably 3 to 5 carbon atoms. The group may be a straight or branched group, and two free atoms may be on the same carbon atom or on different carbon atoms. Examples of such groups include 2-propenylene, 2-methyl-2-propenylene, 2-butenylene, 3-butenylene, 2-pentenylene, 4-pentenylene, 2-methyl-2 butenylene, 2-hexenylene, 2-heptenylene, 3-methyl-2-hexenylene, 3-ethyl-2-pentenylene, 2-methyl-3-hexenylene, 2-octenylene, 4-octenylene, 3-methyl-2-heptenylene, 3,5-dimethyl- 2-hexenylene, 2-nonenylene, 3-methyl-2-octenylene, 3,5-dimethyl- 3-heptylene, 2-decenyl And 3, 7-dimethyl-2-octenylene groups. Alternatively, an alkadieneylene group having 5 to 10 carbon atoms, preferably 5 to 8 carbon atoms may be used. The group may be a straight chain or branched group, the two free atoms may be on the same carbon atom or may be on different carbon atoms. Examples of such groups include 2,4-pentadienylene, 2,4-hexadienylene, 4-methyl-2,4-pentadienylene, 2,4-heptadienylene, 2, 6-heptadienylene, 3 -methyl-2,4-hexadienylene, 2, 6-octadienylene, 3 -methyl-2, 6-heptadienylene, 2 -methyl-2, 4 -heptadienylene, 2, 8-nonadiene Nylene, 3 -methyl-2, 6-octadienylene, 2, 6-decadienylene, 2, 9-decadienylene and 3, 7-dimethyl-2, 6-octadienylene groups.

This may be a C3-C10, preferably C3-C5 alkynylene group. The groups may be straight or branched groups, and the two free valences may be on the same carbon atom or on different carbon atoms. Examples of such groups include 2-propynylene, 2-butynylene, 2-pentynylene, 2-hexynylene, 4-methyl-2-pentynylene, 2-heptinylene, 3-octynylene and 4-decynylene groups. have.

These divalent saturated or unsaturated acyclic hydrocarbon groups may be substituted or unsubstituted, and if substituted the substituents are selected from the group consisting of substituents C as defined above. Originally, except for the number of substitutable positions and imposed by possible steric hindrance, the number of such gaseous substituents is not limited. In general, however, there should preferably be 1 to 4, more preferably 1 or 2 of these substituents. When two or more such substituents are present, they may be the same or different from one another, and examples thereof include the following groups and atoms:

Halogen atoms such as chlorine, bromine, iodine and fluorine atoms; Hydroxyl group; Alkoxy groups having 1 to 4 carbon atoms such as methoxy and ethoxy groups; The aryl moiety may be unsubstituted or, for example, an alkyl group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, a C ₁ to C ₄ alkoxy group, a carboxyl group, a protected carboxyl group, and as exemplified above with respect to substituent A, and Phenoxy, 1-naphthyloxy or 2 having an aryl moiety which may have from 1 to 5, preferably 1 to 3 substituents selected from the group consisting of substituents E which may be the same or different from one another such as amino groups Aryloxy groups having 6 to 14 carbon atoms such as naphthyloxy group; Examples of such groups include 4 -tolyloxy, 4 -hydroxyphenoxy, 4 -chlorophenoxy, 4 -fluorophenoxy, 4 -methoxyphenoxy, 4 -carboxyphenoxy, 4 -methoxycarbonylphenoxy Cis and 4-aminophenoxy groups.

Aralkyl oxy groups in which the alkoxy moiety has 1 to 6 carbon atoms and is substituted with at least one aryl group having 6 to 10, more preferably 6 or 10 ring carbon atoms; An aralkyloxy group which generally has a total of 7 to 13 carbon atoms, for example, an aryl moiety is preferably a phenyl group and an alkyl moiety is preferably C ₁ to C ₃ , such as a benzyloxy or phenethyloxy group; Its aryl moiety may be unsubstituted or, for example, an alkyl group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a carboxyl group, a protected carboxy group, as exemplified above with respect to substituent A, And 1 to 5 substituents selected from the group consisting of substituents E, which may be the same as or different from each other, such as an amino group, may be substituted with 1 to 3 substituents; Examples of such groups include benzyloxy, phenethyloxy, 1-phenylethoxy, 4 -methylbenzyloxy, 4 -hydroxybenzyloxy, 4 -chlorobenzyloxy, 4 -methoxybenzyloxy, 4 -carboxybenzyloxy, 4-methoxycarbonylbenzyloxy and 4-aminobenzyloxy groups are mentioned:

C ₂ -C ₅ aliphatic carboxylic acyloxy groups such as acetoxy, propionyloxy, butyryloxy, valeryloxy, isovaleryloxy and pivaloyloxy groups, especially C ₂ -C ₅ alkanoyloxy groups;

The aryl moiety may be unsubstituted or, for example, an alkyl group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a carboxyl group, a protected carboxyl group and an amino group as exemplified above with respect to substituent A Substituted or unsubstituted C ₇ to C ₁₅ having an aryl moiety which may have from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of substituents E which may be the same or different from one another, such as Aromatic carboxylic acyloxy groups, especially benzoyloxy and naphthoyloxy groups; Examples of such groups include benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy, 4-methylbenzoyloxy, 2-hydroxybenzoyloxy, 4-hydroxy benzoyloxy, 4-chlorobenzoyloxy, 4-methoxy Benzoyloxy, 4-carboxybenzoyloxy, 4-methoxycarbonylbenzoyloxy and 4-aminobenzoyloxy groups are mentioned:

Amino group; Mono- and di-C ₁ to C ₄ alkyl substituted amino groups, where in the case of dialkylamino groups, the two alkyl groups may be the same or different, for example methylamino, ethylamino, propylamino, butylamino , t-butylamino, dimethylamino, methylethylamino, methylbutylamino and diethylamino groups;

The aryl moiety may be unsubstituted, or may be, for example, an alkyl group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a carboxyl group, a protected carboxyl group as exemplified above with respect to substituent A, and Substituted or unsubstituted mono- and di having an aryl moiety which may have from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of substituents E which may be the same or different from one another such as an amino group C ₆ to C ₁₄ aryl substituted amino groups, in particular phenylamino and naphthylamino groups; Examples of such groups include phenylamino, 1-naphthylamino, 2-naphthylamino, 4-tolylamino, 4-hydroxyphenylamino, 4-chlorophenylamino, 4-methoxyphenylamino, 4-carboxyphenylamino , 4-methoxycarbonylphenylamino and 4-aminophenylamino group;

An aralkyl group is an alkyl group having 1 to 6 carbon atoms substituted with at least one aryl group having 6 to 10 ring carbon atoms, and most preferably a mono- and di-aralkyl-substituted having a total of 7 to 9 carbon atoms in the aralkyl group Amino group; In particular substituted or unsubstituted benzylamino and phenethylamino groups, wherein the aryl moiety may be unsubstituted or for example an alkyl group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, a carbon number as exemplified above in connection with substituent A It may have 1 to 5 substituents, preferably 1 to 3 substituents selected from the group consisting of substituents E which may be the same or different from each other, such as 1 to 4 alkoxy groups, carboxyl groups, protected carboxyl groups, and amino groups. ; Examples of such groups include benzylamino, phenethylamino, 4-methylbenzylamino, 4-hydroxybenzylamino, 4-chlorobenzylamino, 4-methoxybenzylamino, 4-carboxybenzylamino, 4-methoxycarbonyl And benzylamino and 4-aminobenzylamino groups.

C ₂ to C ₅ aliphatic carboxylic acyl substituted amino groups, especially C ₂ to C ₅ alkanoylamino groups such as acetamido, propionamido, butyramido, valericamido, isovaleramido and pivaloylamino groups ; C ₇ to C ₁₅ aromatic carboxylic acyl substituted amino groups, in particular substituted or unsubstituted benzamido and naphthoylamido groups, wherein the aryl moiety may be unsubstituted or for example illustrated above in connection with substituent A 1 selected from the group consisting of substituents E which may be the same as or different from each other, such as an alkyl group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a carboxy group, a protected carboxy group, and an amino group as described above. May have from 5 substituents, preferably 1 to 3 substituents; Examples of such groups include benzamido, naphthoylamido, 4-methylbenzamido, 4-hydroxybenzamido, 4-chlorobenzamido, 4-methoxybenzamido, 4-carboxybenzamido , 4-methoxycarbonylbenzamido and 4-aminobenzamido groups.

Carboxyl group; And its protecting group is preferably a protected carboxy group as defined above for the protected group of substituent A, for example; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group; Aralkyloxycarbonyl groups such as benzyloxycarbonyl, diphenylmethoxycarbonyl, 4-nitro benzyloxycarbonyl or 2-nitro benzyloxycarbonyl group; Alkenyloxycarbonyl or haloalkenyloxycarbonyl groups such as allyloxycarbonyl or 2-chloroallyloxycarbonyl group; Haloalkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl or 2,2,2-tribromoethoxycarbonyl group; And substituted silylalkoxycarbonyl groups such as 2-(trimethylsilyl) ethyloxycarbonyl group.

Among these substituents, the following are preferable:

Halogen atom; Hydroxyl group; An alkoxy group having 1 to 4 carbon atoms; Aryloxy groups having 6 to 14 carbon atoms (where the aryl moieties may be the same or different from one another, such as C ₁ -C ₄ alkyl, hydroxy, halogen, C ₁ -C ₄ alkoxy, carboxy, protected carboxy and May have 1 to 3 substituents such as amino); C ₂ -C ₅ aliphatic carboxylic acyloxy group; Amino group; Mono- and di-C ₁ ~ C ₄ alkyl-substituted amino group; C ₂ -C ₅ aliphatic carboxyacyl substituted amino group; C ₇ to C ₁₅ aromatic carboxylic acyl substituted amino groups (wherein the aryl moieties may be the same or different from one another, such as C ₁ -C ₄ alkyl, hydroxy, halogen, C ₁ -C ₄ alkoxy, carboxy, May have 1 to 3 substituents such as protected carboxy and amino); Carboxyl group; And protected carboxyl groups; More preferred are:

Halogen atom; Hydroxyl group; An alkoxy group having 1 to 4 carbon atoms; Amino group; Mono- or di-C ₁ to C ₄ alkyl substituted amino groups; And a C ₂ to C ₅ aliphatic carboxyacyl substituted amino group; And most preferred are a hydroxy group and an alkoxy group having 1 to 4 carbon atoms.

When Y represents an aryl group, the aryl group may be an aryl group having 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms, more preferably 6 or 10 ring carbon atoms, and examples thereof include phenyl, 1-naphthyl and 2- A naphthyl, anthracenyl and phenanthryl group and may be substituted or unsubstituted and, if substituted, have at least one substituent selected from the group consisting of substituents D as defined above and exemplified below. Of these, phenyl and naphthyl groups are preferred, and phenyl groups are most preferred.

When Y represents a cycloalkyl group, a monocyclic or polycyclic (e.g. bicyclic or tricyclic) cycloalkyl group having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and most preferably 5 to 7 carbon atoms (this specification) As used herein, the term includes terphenyl hydrocarbon groups), examples of which may be substituted or unsubstituted and, if substituted, are selected from the group consisting of substituents D defined above and exemplified below Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, pinanyl, bornyl and menthyl groups having at least one substituent.

When Y represents a heterocyclic group, the heterocyclic group may be a simple 5- or 6-membered unsaturated heterocyclic group which may be substituted or unsubstituted containing 1 to 3 oxygen atoms and / or sulfur atoms and / or nitrogen atoms. . When this heterocyclic group contains three hetero-atoms, one, two or three of these hetero-atoms are preferably nitrogen atoms, and the corresponding two, one or zero atoms are oxygen or sulfur atoms. More preferably this heterocyclic group has one or two hetero-atoms; Here, when there is one hetero atom, nitrogen, oxygen, or sulfur atom may be used, or when there are two hetero atoms, one of them is a nitrogen atom, and the other is preferably nitrogen, oxygen or sulfur atom. Examples of unsubstituted groups are 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyridyl, 4- Pyridyl, 2-pyrimidinyl, 5-pyrimidinyl, 2-pyranyl, 4-pyranyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl and 5- An oxazolyl group.

Optionally, the heterocyclic group is a 5- or 6-membered saturated heterocyclic group which contains 1-3 oxygen atoms and / or sulfur atoms and / or nitrogen atoms and may be substituted or unsubstituted. If this group contains three hetero-atoms, one, two or three nitrogen atoms of these are preferred, and the corresponding two, one or zero atoms are preferably oxygen or sulfur atoms. More preferably this group contains 1 or 2 hetero-atoms; Here, when there is one heteroatom, it may be nitrogen, oxygen or sulfur atom, or when there are two hetero-atoms, one of them is nitrogen atom and the other is preferably nitrogen, oxygen or sulfur atom or both oxygen atom. Examples of unsubstituted groups include 2-tetrahydrofuryl, 3-tetrahydrofuryl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 1-pyrrolidinyl, 3-pyrrolidinyl, 2-piperazil, piperi Dino, 2-piperidyl, morpholino, 3-morpholinyl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 1, 4-dioxane-2-day, 1,3,-dioxane -4-days and 1,3-dioxane-5-diary.

Optionally, the heterocyclic group may be a condensed heterocyclic group in which a 5- or 6-membered saturated heterocyclic group containing 1 to 3 oxygen atoms and / or sulfur atoms and / or nitrogen atoms is condensed with a benzene ring. The heterocyclic portion of such a ring system may be fully unsaturated or partially unsaturated, and this group may be substituted or unsubstituted. Examples of unsubstituted groups include 2-benzofuranyl, 2-2H-chromenyl, 2-benzothienyl, 2-indolinyl, 3-indolinyl, 2-dihydrobenzofuranyl, 2-chromanyl, 1, 4 Benzodioxane, 2-yl, 4-quinolyl and 1-isoquinolyl groups.

Such heterocyclic groups are preferably 5- or 6-membered saturated, unsaturated or condensed heterocyclic groups having one or two oxygen atoms and / or nitrogen atoms and / or sulfur atoms, and preferably one or two oxygen atoms and / or nitrogen atoms. And / or 5- or 6-membered saturated or unsaturated heterocyclic groups containing sulfur atoms are most suitable. Any of these heterocyclic groups may be substituted or unsubstituted, and if substituted, the heterocyclic group has at least one substituent selected from the group consisting of substituents D defined above and exemplified below.

Such aryl, cycloalkyl and heterocyclic groups, represented as Y, may be substituted or unsubstituted, and if substituted, the substituents are selected from the group consisting of substituents D as defined above. In principle, there is no restriction on the number of substituents for such groups, except that the number of substitutable positions and the possible steric hindrance is enforced. However, it is usually preferred that there are 1 to 4, more preferably 1 or 2 substituents. When there are two or more such substituents, these substituents may be the same or different from one another, and examples thereof include the following groups and atoms: halogen atoms such as chlorine, bromine, iodine and fluorine atoms; Hydroxyl group; Alkoxy groups having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, S-butoxy and t-butoxy groups; Aryloxy groups having 6 to 14 carbon atoms, such as phenoxy, 1-naphthyloxy and 2-naphthyloxy groups, wherein the aryl moiety may be unsubstituted or for example carbon number as exemplified above with respect to substituent A; 1-5 substituents selected from the group consisting of substituents E which may be the same or different from each other, such as 1-4 alkyl groups, hydroxy groups, halogen atoms, alkoxy groups having 1 to 4 carbon atoms, carboxyl groups, protected carboxyl groups, and amino groups, Preferably, you may have 1-3 substituents; Examples of such groups include 4-tolyloxy, 4-hydroxy, ciphenoxy, 4-chlorophenoxy, 4-fluorophenoxy, 2-methoxyphenoxy, 4-methoxyphenoxy, 4-carboxyphenoxy Cis, 4-methoxycarbonylphenoxy and 4-aminophenoxy groups:

An alkoxy group having 1 to 6 carbon atoms is an aralkyloxy group substituted with at least one aryl group having 6 to 10, more preferably 6 or 10 ring carbon atoms; Preferably an aralkyloxy group having a total of 7 to 13 carbon atoms, the aryl portion thereof being preferably a phenyl group and the alkyl portion being preferably C ₁ to C ₃ , such as benzyloxy and phenethyloxy groups; Its aryl moiety may be unsubstituted or, for example, an alkyl group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a carboxyl group, a protected carboxyl group, as exemplified above with respect to substituent A, And 1 to 5 substituents selected from the group consisting of substituents E, which may be the same or different from each other, such as an amino group, and may be substituted with 1 to 3 substituents; Specific examples of such aralkyloxy groups include benzyloxy, phenethyloxy, 1-phenylethoxy, 4 -methylbenzyloxy, 4 -hydroxybenzyloxy, 4 -chlorobenzyloxy, 4 -methoxybenzyloxy, 4- Carboxybenzyloxy, 4-methoxycarbonylbenzyloxy and 4-aminobenzyloxy groups;

C ₂ -C ₅ aliphatic carboxylic acyloxy groups such as acetoxy, propionyloxy, butyryloxy, valeryloxy, isovaleryloxy and pivaloyloxy groups, in particular C ₂ -C ₅ alkanoyloxy groups;

C ₇ to C ₁₅ aromatic carboxylic acyl oxy groups, especially substituted or unsubstituted benzoyloxy and naphthoyloxy groups, wherein the aryl moiety may be unsubstituted or for example as exemplified above in connection with substituent A 1 to 5 selected from the group consisting of substituents E which may be the same or different from each other, such as an alkyl group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a carboxyl group, a protected carboxyl group, and an amino group A substituent, Preferably it may have 1-3 substituents; Examples of such groups include benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy, 4-methylbenzoyloxy, 2-hydroxybenzoyloxy, 4-hydroxybenzoyloxy, 4-chlorobenzoyloxy, 4-methoxy Benzoyloxy, 4-carboxybenzoyloxy, 4-methoxycarbonylbenzoyloxy and 4-aminobenzoyloxy groups include:

Mercapto group; Alkylthio groups having 1 to 4 carbon atoms such as methylthio and ethylthio groups; Alkylthio groups having 6 to 14 carbon atoms, in particular substituted or unsubstituted phenylthio and naphthylthio groups, wherein the aryl moiety may be unsubstituted or for example have 1 to 4 carbon atoms as exemplified above in connection with substituent A 1-5 substituents selected from the group consisting of substituents E which may be the same or different from each other, such as an alkyl group, a hydroxy group, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a carboxyl group, a protected carboxyl group, and an amino group It may have 1-3 substituents; Examples of such groups include phenylthio, 1-naphthylthio, 2-naphthylthio, 4-tolylthio, 4-hydroxyphenylthio, 4-chlorophenylthio, 4-methoxyphenylthio, 4-carboxyphenylthio , 4-methoxycarbonylphenylthio and 4-aminophenylthio groups include:

An aralkylthio group in which an alkylthio group having 1 to 6 carbon atoms is substituted with at least one aryl group having 6 to 10 ring carbon atoms, preferably 6 or 10 ring carbon atoms; The aralkylthio group preferably has a total of 7 to 13 carbon atoms; Especially preferred is a benzylthio and phenethylthio group which may be substituted or unsubstituted; In such groups, the aryl moiety may be unsubstituted or have, for example, 1 to 5 substituents, preferably 1 to 3 substituents selected from the group consisting of substituents E, which may be the same or different from one another, and Examples of the substituent include an alkyl group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a carboxy group, a protected carboxy group, and an amino group as exemplified above with respect to the substituent A; Specific examples of such aralkylthio groups include benzylthio, phenethylthio, 4-methylbenzylthio, 4-hydroxybenzylthio, 4-chlorobenzylthio, 4-methoxybenzylthio, 4-carboxybenzylthio, 4 Methoxycarbonylbenzylthio and 4-aminobenzylthio groups;

Amino group; Mono- and di-C ₁ to C ₄ alkyl substituted amino groups such as methylamino, dimethylamino and diethylamino groups; Mono- and di-C ₆ to C ₁₄ allyl substituted amino groups, especially substituted or unsubstituted phenylamino and naphthylamino groups, wherein the aryl moiety may be unsubstituted or for example exemplified above in connection with substituent A 1-5 selected from the group consisting of substituents E which may be the same or different from each other, such as an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a carboxyl group, a protected carboxyl group, and an amino group as described above May have 3 substituents, preferably 1 to 3 substituents; Examples of such groups include phenylamino, 1-naphthylamino, 2-naphthylamino, 2-tolylamino, 4-tolylamino, 4-hydroxyphenylamino, 4-chlorophenylamino, 4-methoxyphenylamino, 4-carboxyphenylamino, 4-methoxycarbonylphenylamino and 4-aminophenylamino groups; Mono- and di-aralkyl-substituted amino groups wherein the aralkyl moiety is an alkyl group having 1 to 6 carbon atoms substituted with at least one (preferably only one) aryl substituent; In particular benzylamino and phenethylamino groups are preferred and may be substituted or unsubstituted; Wherein the aryl moiety may be unsubstituted or for example an alkyl group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a carboxyl group, a protected carboxyl group, as exemplified above with respect to substituent A, And 1 to 5 substituents selected from the group consisting of substituents E which may be the same as or different from each other, such as an amino group, preferably 1 to 3 substituents; Specific examples of such an aralkylamino group include benzylamino, phenethylamino, 4-methylbenzylamino, 4-hydroxybenzylamino, 4-chlorobenzylamino, 4-methoxybenzylamino, 4-carboxybenzylamino, 4-memethyl Oxycarbonylbenzylamino and 4-aminobenzylamino groups;

C ₂ to C ₅ aliphatic carboxylic acyl substituted amino groups such as acetamido, propionamido, butyramido, valericamido, isovaleramido and pivaloylamino groups, in particular C ₂ to C ₅ alkanoylamino groups ; C ₇ to C ₁₅ aromatic carboxylic acyl substituted amino groups, in particular substituted or unsubstituted benzamido and naphthoylamido groups, wherein the aryl moiety may be unsubstituted or for example illustrated above in connection with substituent A 1 to 4 selected from the group consisting of substituents E which may be the same as or different from each other, such as an alkyl group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a carboxy group, a protected carboxy group, and an amino group. Five substituents, preferably 1-3 substituents; Examples of such groups include benzamido, naphthoylamido, 4-methylbenzamido, 4-hydroxybenzamido, 4-chlorobenzamido, 4-methoxybenzamido, 4-carboxybenzamido , 4-methoxycarbonylbenzamido and 4-aminobenzamido groups

Nitro group; Cyano group; Carboxyl group; A protecting group is, for example, an alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl group or the like; Aralkyloxycarbonyl groups such as benzyloxycarbonyl group, diphenylmethoxycarbonyl, 4-nitrobenzyloxycarbonyl and 2-nitrobenzyloxycarbonyl group; Alkenyloxycarbonyl and haloalkenyloxycarbonyl groups such as allyloxycarbonyl and 2-chloroallyloxycarbonyl group; Haloalkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl and 2,2,2-tribromoethoxycarbonyl group; Protected carboxy groups preferably defined above with respect to protecting groups of substituent A, such as substituted silylalkoxycarbonyl groups, such as 2-(trimethylsilyl) ethoxycarbonyl group; C ₁ -C ₅ alkyl groups which may be linear or branched, such as methyl, ethyl, propyl, butyl and pentyl groups; Halogen-substituted C ₁ to C ₅ alkyl groups which may be linear or branched, such as trifluoromethyl group; C ₁ to C ₅ hydroxyalkyl groups such as hydroxymethyl and hydroxyethyl groups; And at least one, and preferably C ₁ -C ₅ alkyl group having only one C ₂ -C ₅ aliphatic carboxylic acyloxy substituent; Examples of alkyl groups include those exemplified above with respect to substituent B, and examples of acyloxy groups include those exemplified above with respect to substituent A; Examples of these acyloxyalkyl groups include acetoxymethyl, 1- and 2-propionyloxyethyl and 5-butyryloxypentyl groups.

Preferred among these substituents are: halogen atoms; Hydroxyl group; A C ₁ to C ₄ alkoxy group; C ₆ to C ₁₄ aryloxy group (wherein the aryl moiety is unsubstituted or one to three substituents that may be the same or different from one another, such as C ₁ to C ₄ alkyl, hydroxy, halogen, C ₁ to C ₄ alkoxy) , Carboxy, protected carboxy and amino substituents.); A C ₇ to C ₁₃ aralkyloxy group wherein the aryl moiety is unsubstituted or may be the same as or different from one to three substituents, such as C ₁ to C ₄ alkyl, hydroxy, halogen, C ₁ to C ₄ Alkoxy, carboxy, protected carboxy and amino substituents); C ₂ -C ₅ aliphatic carboxylic acyloxy group; C ₇ to C ₁₅ aromatic carboxylic acyloxy groups, wherein the aryl moiety is unsubstituted or the same or different from one to three substituents, such as C ₁ to C ₄ alkyl, hydroxy, halogen, C ₁ to C ₄ Alkoxy, carboxy, protected carboxy and amino substituents); Mercapto group; C ₁ ~ C ₄ alkylthio groups; Amino group; Mono- and di-C ₁ ~ C ₄ alkyl-substituted amino group; C ₂ -C ₅ aliphatic carboxylic acylamino group; Nitro group; Cyano group; Carboxyl group; Protected carboxyl groups; C ₁ -C ₅ alkyl group; Halogen-substituted C ₁ to C ₅ alkyl groups; C ₁ -C ₅ hydroxyalkyl group; And C ₂ -C ₅ aliphatic carboxylic acyloxy-substituted C ₁ -C ₅ alkyl groups.

Among these, more preferable substituents are; Halogen atom; Hydroxyl group; C ₁ -C ₄ alkoxy group; C ₆ to C ₁₄ aryloxy group, wherein the aryl moiety is unsubstituted or may have 1 to 3 substituents which may be the same or different from each other, such as C ₁ to C ₄ alkyl, hydroxy, halogen, C ₁ to C ₄ alkoxy , Carboxy, protected carboxy and amino substituents.); C ₇ to C ₁₃ aralkyloxy group, wherein the aryl moiety is unsubstituted or may have 1 to 3 substituents that may be the same or different from each other, such as C ₁ to C ₄ alkyl, hydroxy, halogen, C ₁ to C ₄ Alkoxy, carboxy, protected carboxy and amino substituents.); Amino group; Mono- and di-C ₁ ~ C ₄ alkyl-substituted amino group; C ₂ -C ₅ aliphatic carboxylic acylamino group; Nitro group; Cyano group; Carboxyl group; Protected carboxyl groups; C ₁ -C ₅ alkyl group; A C ₁ to C ₅ haloalkyl group; C ₁ -C ₅ hydroxyalkyl group; And C ₂ -C ₅ aliphatic carboxylic acyloxy-substituted C ₁ -C ₅ alkyl groups.

Most preferable among them are halogen atoms; Hydroxyl group; C ₁ -C ₄ alkoxy group; Amino group; Mono- and di-C ₁ ~ C ₄ alkyl-substituted amino group; C ₂ -C ₅ aliphatic carboxylic acylamino group; Nitro group; A C ₁ to C ₅ haloalkyl group; And a C ₁ to C ₅ hydroxyalkyl group.

Since the compounds of the present invention contain essentially one or more carboxyl groups, these compounds are acids and therefore can form salts and esters. There is no particular limitation on the nature of such salts and esters, but for monotherapeutic use it must be pharmaceutically acceptable, which is reduced activity (or unacceptably reduced) relative to free acid as is known to those skilled in the art. Activity) or increased toxicity (or unacceptably increased toxicity). Even when these compounds are for non-therapeutic uses, for example when used as intermediates for the preparation of other compounds, these limitations do not apply.

Examples of ester groups include the following:

The above examples for alkyl groups which may be represented by C ₁ to C ₂₀ , more preferably C ₁ to C ₁₀ , even more preferably C ₁ to C ₇ and most preferably C ₁ to C ₅ alkyl groups such as X Ones and higher alkyl groups known in the art such as dodecyl, tridecyl, pentadecyl, octadecyl, nonadecyl and icosyl groups, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl And pentyl groups, but most preferably methyl, ethyl and t-butyl groups; C ₃ to C ₇ cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups; It may be substituted or unsubstituted, although an unsubstituted group is preferred but substituted, the alkyl moiety is C ₁ to C ₃ and the aryl moiety is C ₆ to C ₁₄ carbocyclic aromatic having at least one substituent D as defined and exemplified above. Aralkyl group which is group; Generally, aralkyl groups of a total of C ₇ to C ₉ are preferred; Examples of aralkyl groups include benzyl, phenethyl, 1 -phenylethyl, 3 -phenylpropyl, 2 -phenylpropyl, 1 -naphthylmethyl, 2 -naphthylmethyl, 2-(1 -naphthyl) ethyl, 2-( 2-naphthyl) ethyl, benzhydryl (ie diphenylmethyl), triphenylmethyl, bis (o-4 trophenyl) methyl, 9- anthrylmethyl, 2, 4, 6-trimethylbenzyl, 4-bro Mobenzyl, 2-nitrobenzyl, 4-nitrobenzyl, 3-nitrobenzyl, 4-methoxybenzyl and piperonyl groups; C ₂ to C ₁₀ , more preferably C ₃ to C ₁₀ and more preferably C ₃ to C ₅ alkenyl groups such as vinyl, allyl, 2-methylallyl, 2-propenyl, isopropenyl, 1- Butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4- Hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, 1-nonenyl and 1-decenyl groups, among these preferably vinyl, allyl, 2 -methylallyl, 1 -propenyl, isopro Phenyl and butenyl groups, most preferably allyl and 2-methylallyl groups; A halogenated alkyl group of C ₁ to C ₆ , preferably C ₁ to C ₄ , wherein the alkyl moiety is as defined and exemplified for the alkyl group, the halogen atom being a chlorine, fluorine, bromine or iodine halogenated alkyl group, Chloromethyl, bromomethyl, iodomethyl, fluoromethyl, trichloromethyl, trifluoromethyl, dichloromethyl, difluoromethyl, 2, 2, 2-trichloroethyl, 2-haloethyl (e.g. For example, 2-chloroethyl, 2-fluoroethyl, 2-bromoethyl, or 2-iodoethyl), 2, 2-dibromoethyl, and 2, 2, 2-tribromoethyl group; Substituted silylalkyl groups, wherein the alkyl moiety is as defined and exemplified above and the silyl group is selected from a C ₁ to C ₆ alkyl group and a phenyl group which is unsubstituted or has one or more substituents selected from substituents D as defined and exemplified above. Substituted silylalkyl groups having up to 3 substituents, such as 2-trimethylsilylethyl group; A phenyl group which is unsubstituted or preferably substituted with one or more C ₁ to C ₄ alkyl groups or acylamino groups, for example, phenyl, tolyl and benzamidophenyl groups; Penacyl groups which may be unsubstituted or have one or more substituents D as defined and exemplified above, for example penacyl group itself or p-bromophenacyl group; Ring and acyclic terphenyl groups such as geranyl, neryl, linalyl, pityl, menthyl (particularly m-and p-methyl), tusyl, caryl, pinanyl, bornyl, norcaryl, noropinanyl, norbor Neyl, Mentenyl, Campenyl and Norbornenyl groups; Alkoxy moieties are C ₁ to C ₆ , preferably C ₁ to C ₄ , which may themselves be substituted by one unsubstituted alkoxy group, such as methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxy Methyl, butoxymethyl and methoxyethoxymethyl groups; The acyl group is preferably an alkanoyl group, more preferably a C ₂ to C ₆ alkanoyl group, and the alkyl moiety is C ₁ to C ₆ , preferably C ₁ to C ₄ , an aliphatic acyl, oxyalkyl group such as acetoxy Methyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, 1-pivaloyloxyethyl, 1-acetoxyethyl, 1-isobutyryloxyethyl, 1-pivalo Yloxypropyl, 2-methyl-1-pivaloyloxypropyl, 2-pivaloyloxypropyl, 1-isobutyryloxyethyl, 1-isobutyryloxypropyl, 1-acetoxypropyl, 1-acetoxy 2-methylpropyl, 1-propionyloxyethyl, 1-propionyloxypropyl, 2-acetoxypropyl and 1-butyryloxyethyl group; The acyl group is preferably an alkanoyl group, more preferably a C ₂ to C ₆ alkanoyl group, the cycloalkyl substituent is C ₃ to C ₇ , and the alkyl moiety is C ₁ to C ₆ , preferably C ₁ to C ₄ phosphorus cycloalkyl-substituted aliphatic acyloxyalkyl groups such as (cyclohexylacetoxy) methyl, 1-(cyclohexylacetoxy) ethyl, 1-(cyclohexylacetoxy) propyl, 2 -methyl-1-(cyclohexylacetyl) Methoxy) propyl, (cyclopentylacetoxy) methyl, 1- (cyclopentylacetoxy) ethyl, 1- (cyclopentylacetoxy) propyl, and 2-methyl-1-(cyclopentylacetoxy) propyl group; The alkoxy part is C ₁ ~ C _10, preferably C ₁ ~ C _6, and more preferably C ₁ ~ C _4, and the alkyl part is C ₁ ~ C _6, preferably C ₁ ~ C ₄ alkoxycarbonyl Oxyalkyl groups, in particular 1- (alkoxycarbonyloxy) ethyl groups such as 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxy Ethyl, 1-butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl, 1-S-butoxycarbonyloxyethyl, 1-t-butoxycarbonyloxyethyl, 1- (1-ethylpropoxy Carbonyloxy) ethyl and other alkoxycarbonylalkyl groups in which both the 1- (1,1-dipropylbutoxycarbonyloxy) ethyl group and the alkoxy and alkyl groups are C ₁ to C ₆ , preferably C ₁ to C ₄ , such as 2-methyl-l- (isopropoxycarbonyloxy) propyl, 2- (isopropoxycarbonyloxy) propyl, isoprop Foxoxycarbonyloxymethyl, t-butoxycarbonyloxymethyl, methoxycarbonyloxymethyl and ethoxycarbonyloxy methyl groups;

The cycloalkyl group is C ₃ to C ₁₀ , preferably C ₃ to C ₇ , mono- or poly-cyclic, and at least one (preferably only one) C ₁ to C ₄ alkyl group (eg the examples above) Optionally substituted with one alkyl group) and the alkyl moiety is C ₁ to C ₆ more preferably C ₁ to C ₄ (eg those selected from the alkyl groups exemplified above) and most preferably methyl, ethyl or Propyl cycloalkylcarbonyloxyalkyl and cycloalkyloxycarbonyloxyalkyl groups such as 1-methylcyclohexylcarbonyloxymethyl, 1-methylcyclohexyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxymethyl, Cyclopentylcarbonyloxymethyl, 1 -cyclohexyloxycarbonyloxyethyl, 1 -cyclohexylcarbonyloxyethyl, 1 -cyclopentyloxycarbonyloxyethyl, 1 -cyclopentcarbonyloxyethyl, 1 -cyclohep Yloxycarbonyloxyethyl, 1 -cycloheptyl carbonyloxyethyl, 1 -methylcyclopentylcarbonyloxymethyl, 1 -methylcyclopentyloxycarbonyloxymethyl, 2 -methyl-1-(1 -methylcyclohexyl Carbonyloxy) propyl, 1- (1-methylcyclohexylcarbonyloxy) propyl, 2- (1-methylcyclohexylcarbonyloxy) propyl, 1- (cyclohexylcarbonyloxy) propyl, 2- (cyclohexyl Carbonyloxy) propyl, 2-methyl-l- (l-methylcyclopentylcarbonyloxy) propyl, l- (l-methylcyclopentylcarbonyloxy) propyl, 2- (l-methylcyclopentylcarbonyloxy) Propyl, 1-(cyclopentylcarbonyloxy) propyl, 2-(cyclopentylcarbonyloxy) propyl, 1-(1-methylcyclopentylcarbonyloxy) ethyl, 1-(1-methylcyclopentylcarbonyloxy) Propyl, adamantyloxycarbonyloxymethyl, adamantylcarbonyloxymethyl, 1-adamantyloxycarbonyl jade A cyethyl and 1-adamantylcarbonyloxyethyl group;

Cycloalkylalkoxycarbonyloxyalkyl groups having one cycloalkyl substituent wherein the alkoxy group is C ₃ to C ₁₀ , preferably C ₃ -C ₇ and is mono- or poly-cyclic, for example cyclopropylmethoxycarbonyloxy Methyl, cyclobutyl methoxycarbonyloxymethyl, cyclopentylmethoxycarbonyloxymethyl, cyclohexylmethoxycarbonyloxymethyl, 1-(cyclopropylmethoxycarbonyloxy) ethyl, 1-(cyclobutylmethoxycarbon Carbonyloxy) ethyl, 1- (cyclopentylmethoxycarbonyloxy) ethyl, and 1- (cyclohexylmethoxycarbonyloxy) ethyl group; A terphenyl group is as exemplified above, preferably a terphenylcarbonyloxyalkyl and a terphenyloxycarbonyloxyalkyl group, for example, 1- (menthyloxycarbonyloxy) ethyl, 1- (menthyl) Carbonyloxy) ethyl, menthyloxycarbonyloxymethyl, methylcarbonyloxymethyl, 1- (3-pinanyloxycarbonyloxy) ethyl, 1- (3-pinanylcarbonyloxy) ethyl, 3-pinanyl Oxycarbonyloxymethyl and 3-pinanylcarbonyloxymethyl group; Each alkyl group (which may be the same or different) may be substituted with one or more substituents D as defined and exemplified by 5-alkyl or 5-phenyl which are C ₁ to C ₆ , preferably C ₁ to C ₄ . Can be] (2-oxo-1,3-dioxolen-4-yl) alkyl group, for example (5-methyl-2-oxo-1,3-dioxolene-4yl) methyl, (5-phenyl) -2-oxo-1, 3-dioxolene-4-yl) methyl, (5-isopropyl-2-oxo-1, 3-dioxolene-4-yl) methyl, (5-t-butyl-2- Oxo-1,3-dioxolene-4-yl) methyl and 1- (5-methyl-2-2-oxo-1,3-dioxolene-4-yl) ethyl group; And other groups, in particular groups which can be easily removed in vivo, such as phthalidyl, indanyl and 2-oxo-4, 5, 6,7-tetrahydro-1,3-benzodioxolelene-4 diaries In the group, Preferably; Alkyl esters, especially those in which the alkyl group is C ₁ to C ₆ , such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl esters; Alkenyl esters, especially those with alkenyl groups C ₃ or C ₄ , such as allyl and metalyl esters; And aralkyl groups, preferably aralkyl esters as described above with respect to X, such as benzyl and phenethyl esters. Of these, most preferred are methyl, ethyl, allyl and benzyl esters.

Examples of pharmaceutically acceptable salts of carboxylic acids of Formula 1 include metal salts, amino acid salts and amine salts. Examples of metal salts include; Alkali metal salts such as sodium and potassium salts; Alkaline earth metal salts such as calcium and magnesium salts; And other metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts and cobalt salts. Of these, alkali metal salts, alkaline earth metal salts and aluminum salts are preferred, and most preferably sodium salts, potassium salts, calcium salts and aluminum salts. Examples of amino acid salts include salts with basic amino acids such as arginine, lysine, histidine, α, γ-diaminobutyric acid and ornithine. Examples of amine salts include t-octylamine, dibenzylamine, dicyclohexylamine, morpholine, D-phenylglycine alkyl esters and D-glucosamine salts. Among these, sodium, potassium, and calcium salts are preferred.

Preferred compounds of the invention are as follows:

(A) a compound of formula 1 and pharmaceutically acceptable salts and esters thereof:

R represents a hydrogen atom, a methyl group or a hydroxy group; X is a C ₁ to C ₁₀ alkyl group, a C ₃ to C ₁₀ alkenyl group, a C ₃ to C ₁₀ cycloalkyl group, a phenyl group, a C ₇ to C ₉ aralkyl group or one or two selected from the group consisting of oxygen, sulfur and nitrogen heteroatoms An unsaturated heterocyclic group having 5 or 6 ring atoms, which is a hetero atom, wherein the alkyl and alkenyl group is unsubstituted or has 1 to 4 substituents selected from the group consisting of substituents A ¹ as defined below; , Phenyl, aralkyl and heterocyclic groups are unsubstituted or have 1 to 4 substituents selected from the group consisting of substituents B as defined above; A represents a single bond, a C ₁ -C ₁₀ alkylene group, a C ₃ -C ₁₀ alkenylene group, a C ₅ to C ₁₀ alkadienylene group or a C ₃ to C ₅ alkynylene group, wherein the alkylene and alkenylene , Alkadienylene and alkynylene groups are unsubstituted or have 1 or 2 substituents selected from the group consisting of substituents C ¹ defined below; Y represents a C ₆ to C ₁₀ aryl group, a C ₃ to C ₈ cycloalkyl group, each of which has one or two substituents each selected from the group consisting of substituents D ¹ which are unsubstituted or defined below:

[Substituent A ¹ ]

Halogen atom, hydroxy group, C ₁ to C ₄ alkoxy group, C ₂ to C ₅ aliphatic carboxylic acyloxy group, amino group, carboxyl group and protected carboxyl group;

[Substituent C ¹ ]

Halogen atom, hydroxy, C ₁ to C ₄ alkoxy group, C ₆ to C ₁₄ aryloxy group, C ₂ to C ₅ aliphatic carboxyl acyloxy group, amino group, monoalkyl having 1 to 4 carbon atoms in each alkyl part- And di-alkyl-substituted amino groups, C ₂ to C ₅ aliphatic carboxylic acylamino groups, C ₇ to C ₁₅ aromatic carboxylic acylamino groups, carboxyl groups and protected carboxyl groups, wherein the aryloxy and aromatic carboxylic acylamino groups The aryl group of has unsubstituted or has 1 to 3 substituents selected from the group consisting of substituents E ¹ as defined below:

[Substituent D ¹ ]

Halogen atom, hydroxy group, C ₁ to C ₄ alkoxy group, C ₆ to C ₁₄ aryloxy group, C ₇ to C ₉ aralkyloxy group, C ₂ to C ₅ aliphatic carboxylic acyloxy group, C ₇ to C ₁₅ Aromatic carboxylic acyloxy group, mercapto group, C ₁ to C ₄ alkylthio group, amino group, mono- and di-alkyl-substituted amino group having 1 to 4 carbon atoms in each alkyl portion, C ₂ to C ₅ aliphatic car Cyclolic acylamino group, nitro group, cyano group, carboxyl group, protected carboxyl group, C ₁ to C ₅ alkyl group, C ₁ to C ₅ haloalkyl group, C ₁ to C ₅ hydroxyalkyl group and acyl moiety C ₂ to C ₅ aliphatic car An acyloxy alkyl group having a cyclic acyl group and an alkyl moiety of C ₁ to C ₅ , wherein the aryl group of the aryloxy, aralkyloxy and aromatic carboxylic acyloxy groups is unsubstituted or defined from the group consisting of the substituents E ¹ defined below. Having 1 to 3 substituents selected.

[Substituent E ¹ ]

C ₁ -C ₄ alkyl group, hydroxy, halogen, C ₁ -C ₄ alkoxy group, carboxyl group, protected carboxyl group and amino group.

(B) the compound of formula 1 and pharmaceutically acceptable salts and esters thereof; R and X are as defined in (A) above; A is a C ₁ to C ₁₀ alkylene group, a C ₃ to C ₁₀ alkenylene group, a C ₅ to C ₁₀ alkadienylene group or a C ₃ to C ₅ alkynylene group, and the alkylene, alkenylene, alkadienylene and alkoxy The nylene group has one or two substituents unsubstituted or selected from the group consisting of substituents C ¹ as defined in (A) above; Y is a heterocyclic group having 5 or 6 ring atoms where 1 to 3 are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur heteroatoms, or 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur heteroatoms and benzene A heterocyclic group having 5 or 6 ring atoms bonded to the ring, wherein the heterocyclic group has 1 or 2 substituents selected from the group consisting of substituents D ¹ which are unsubstituted or defined in (A) above.

(C) the compound of formula (1) and pharmaceutically acceptable salts and esters thereof: R and X are as defined above in (A); A is a C ₁ to C ₁₀ alkylene group, a C ₃ to C ₁₀ alkenylene group, a C ₅ to C ₁₀ alkadienylene group or a C ₃ to C ₁₀ alkynylene group, and the alkenylene, alkadienylene and alkynylene group are not provided. Ring or one or two substituents selected from the group consisting of substituents C ¹ as defined in (A) above; Y is a hydrogen atom.

Even more preferred compounds of the invention are:

(D) the compound of formula 1 and pharmaceutically acceptable salts and esters thereof; R is a hydrogen atom, a methyl group or a hydroxy group; X is a C ₁ to C ₁₀ alkyl group, C ₃ to C ₁₀ alkenyl group or C ₃ to C ₇ cycloalkyl group, wherein the alkyl and alkenyl group is 1 or 2 unsubstituted or selected from the group consisting of substituents A ² defined below Substituents and the cycloalkyl group is unsubstituted or has 1 or 2 substituents selected from the group consisting of substituents B ¹ as defined below; A is a single bond, a C ₁ to C ₅ alkylene group, a C ₃ to C ₅ alkenylene group or a C ₅ to C ₈ alkadienylene group, wherein the alkylene, alkenylene and alkadienylene groups are unsubstituted or defined below Having 1 or 2 substituents selected from the group consisting of substituents C ² ; Y is a C ₆ -C ₁₀ aryl group or a C ₅ -C ₇ cycloalkyl group, which can each have one or two substituents independently unsubstituted or independently selected from the group consisting of substituents D ² defined below:

[Substituent A ² ]

Halogen atom, hydroxy group, C ₂ -C ₅ aliphatic carboxylic acyloxy group, carboxyl group and protected carboxyl group;

[Substituent B ¹ ]

Halogen atom, hydroxy, C ₁ to C ₄ alkoxy group, C ₂ to C ₅ aliphatic carboxylic acyloxy group, C ₁ to C ₅ alkyl group and C ₁ to C ₅ haloalkyl group;

[Substituent C ² ]

A halogen atom, a hydroxy group, a C ₁ to C ₄ alkoxy group, an amino group, a mono- and di-alkyl-substituted amino group having 1 to 4 carbon atoms in each alkyl portion, and a C ₂ to C ₅ aliphatic carboxylic acylamino group; And

[Substituent D ² ]

Halogen atom, hydroxy group, C ₁ to C ₄ alkoxy group, C ₆ to C ₁₄ aryloxy group, C ₇ to C ₉ aralkyloxy group, amino group, mono- and di-alkyl having 1 to 4 carbon atoms in each alkyl group Substituted amino groups, C ₂ to C ₅ aliphatic carboxylic acylamino groups, nitro groups, cyano groups, carboxy groups, protected carboxyl groups, C ₁ to C ₅ alkyl groups, C ₁ to C ₅ haloalkyl groups, C ₁ to C ₅ hydroxy An alkyl group and an acyloxyalkyl group in which the acyl moiety is a C ₂ to C ₅ aliphatic carboxylic acyl group and the alkyl moiety is C ₁ to C ₅ , wherein the aryl groups of the aryloxy, aralkyloxy and aromatic carboxylic acyloxy groups are unsubstituted or It has 1 to 3 substituents selected from the group consisting of substituents E ¹ as defined in the above (A).

(E) the compound of formula (1) and pharmaceutically acceptable salts and esters thereof: R and X are as defined above in (B); A is a C ₁ to C ₅ alkylene group, a C ₃ to C ₅ alkenylene group or a C ₅ to C ₈ alkadienylene group, wherein the alkylene, alkenylene and alkadienylene groups are unsubstituted or Has 1 or 2 substituents each selected from the group consisting of defined substituents C ² ; Y is a heterocyclic group having 5 or 6 ring atoms where 1 or 2 are heteroatoms selected from the group consisting of nitrogen and oxygen heteroatoms, or ring atoms having 1 or 2 heteroatoms selected from the group consisting of nitrogen and oxygen heteroatoms A heterocyclic group having 5 or 6 and bonded to a benzene ring, wherein the heterocyclic group has 1 or 2 substituents each unsubstituted or selected from the group consisting of substituents D ² as defined in (D) above.

(F) the compound of formula (1) and pharmaceutically acceptable salts and esters thereof: R and X are as defined in (D) above; A is a C ₁ to C ₁₀ alkylene group, a C ₃ to C ₁₀ alkenylene group or a C ₅ to C ₁₀ alkadienylene group, wherein the alkenylene and alkadienylene group are unsubstituted or a substituent C ^{2 as} defined in (D) above. Having 1 or 2 substituents each selected from the group consisting of; Y represents a hydrogen atom.

Among the compounds of the present invention described above, even more preferred compounds are;

(G) a compound of formula 1 and pharmaceutically acceptable salts and esters thereof; R represents a hydrogen atom; X is a C ₁ to C ₇ alkyl group, a C ₃ to C ₅ alkenyl group or a C ₃ to C ₇ cycloalkyl group, wherein the alkyl and alkenyl group is unsubstituted or independently selected from the group consisting of substituents A ³ defined below; Having two substituents said cycloalkyl group is unsubstituted or has one or more substituents selected from the group consisting of substituents B ² defined below; A is a single bond, a C ₁ to C ₅ alkylene group or a C ₃ to C ₅ alkenylene group, which may each have one or two substituents independently unsubstituted or independently selected from the group consisting of substituents C ³ as defined below. ;

Y represents a C ₆ to C ₁₀ aryl group or a C ₅ to C ₇ cycloalkyl group, each having one or two substituents independently selected from the group consisting of substituents D ³ , which are unsubstituted or defined below:

[Substituent A ³ ]

Halogen atom and carboxy group;

[Substituent B ² ]

Halogen atom and C ₁ to C ₅ haloalkyl group;

[Substituent C ³ ]

A hydroxyl group and a C ₁ to C ₄ alkoxy group;

[Substituent D ³ ]

A halogen atom, a hydroxyl group, a C ₁ to C ₄ alkoxy group, an amino group, a mono- and di-alkyl-substituted amino group having 1 to 4 carbon atoms in each alkyl portion, a C ₂ to C ₅ aliphatic carboxylic acylamino group, a nitro group, C ₁ ~ C ₅ alkyl group, C ₁ ~ C ₅ haloalkyl group, and C ₁ ~ C ₅ hydroxyalkyl group;

(H) a compound of formula 1 and pharmaceutically acceptable salts and esters thereof; R and X are as defined in (G) above; A is a C ₁ to C ₅ alkylene group or a C ₃ to C ₅ alkenylene group, which may each have one or two substituents each unsubstituted or selected from the group consisting of substituents C ³ as defined in (G) above; ; Y is a heterocyclic group having 5 or 6 ring atoms wherein 1 or 2 are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur heteroatoms which are unsubstituted or each selected from the group consisting of substituents D ³ as defined in (G) above It may have 1 or 2 substituents:

(I) the compound of formula (1) and pharmaceutically acceptable salts and esters thereof: R and X are as defined in (G) above; A is a C ₁ -C ₁₀ alkylene group, a C ₃ -C ₇ alkenylene group or a C ₅ -C ₈ alkadienylene group, each of which is unsubstituted or independent from the group consisting of substituents C ³ as defined in (G) above. May have 1 or 2 substituents selected from; Y is a hydrogen atom.

Even more desirable is:

(J) the compound of formula (1) and pharmaceutically acceptable salts and esters thereof: R is a hydrogen atom; X is C ₁ ~ C ₇ alkyl group; A is C ₁ ~ C ₅ alkylene group and; Y is a C ₆ to C ₁₀ aryl group or a C ₅ to C ₇ cycloalkyl group, which are unsubstituted or substituted by one or two substituents selected from the group consisting of substituents D ⁴ as defined below;

[Substituent D ⁴ ]

A halogen atom, a hydroxy group, C ₁ ~ C ₄ alkoxy group and C ₁ ~ C ₅ alkyl group.

Most preferred compounds of the present invention are;

(K) the compound of formula 1 and pharmaceutically acceptable salts and esters thereof; R is a hydrogen atom; X is C ₁ ~ C ₇ alkyl group; A is C ₁ ~ C ₅ alkylene group and; Y is a C ₆ to C ₁₀ aryl group which is unsubstituted or substituted by one or two substituents selected from the group consisting of substituents D ⁵ defined below:

[Substituent D ⁵ ]

A halogen atom and a C ₁ ~ C ₄ alkoxy group.

(L) the compound of formula 1 and pharmaceutically acceptable salts and esters thereof;

R, X and A are as defined in the above (K): Y represents a heterocyclic group having 5 to 6 ring atoms having 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur heteroatoms, which is carbon number It may be unsubstituted or have 1 or 2 substituents each selected from the group consisting of 1 to 5 alkyl groups.

(M) the compound of formula (1) and pharmaceutically acceptable salts and esters thereof: R and X are as defined above in (K); A represents an alkylene group having 1 to 10 carbon atoms; Y represents a hydrogen atom.

Examples of specific compounds of the present invention are compounds of formula 1 wherein R, X, Y and A are defined in Table 1 below. Where appropriate, the compounds of the invention are hereinafter indicated by the addition of numbers to the tables below.

Among the above compounds, preferred compound numbers are 1, 6, 17, 18, 39, 45, 47, 54, 60, 61, 122, 123, 124, 126, 128, 129, 132, 134, 135, 136, 137 , 138, 139, 140, 141 and 142; More preferred compound numbers are 1, 39, 54, 126, 135, 136, 137, 138, 139, 140, 141 and 142.

Most preferred specific compounds are

The compounds of the present invention may contain or contain several subsidiary carbon atoms, which generate various optical isomers. In addition, the presence of the oxime moiety (= NO-A-Y) is present in all compounds of the formula I free acid and salts and esters thereof, both in the syn and anti-stereoisomers. Although all of these isomers are shown here in a single plane, all of the individual isomers and mixtures thereof are to be considered as present invention. If the compounds are prepared by stereospecific synthetic techniques, each isomer may be prepared. Otherwise, a mixture of isomers can usually be obtained. In this case, a mixture of the isomers may be used or the individual isomers may be separated by known separation techniques.

The compounds of the present invention can be prepared by various methods known in the art in this form of preparation.

Wherein X, Y, R and A are as defined above and R ^a represents an alkyl, alkenyl or aralkyl group as defined and exemplified above with respect to the ester group.

For example, the compound of formula 2 is oxidized to obtain a compound of formula 3, if necessary, the compound of formula 3 is de-esterified to obtain a compound of formula 1, and if necessary, formula 3 or formula 1 The compounds of can be prepared by converting them to esters or salts.

In more detail the proposed method for the preparation of the compounds of the invention is illustrated in the following reaction scheme:

Wherein X, Y, R, R ^a and A are as defined above.

Compounds of formula (IV) used as starting materials in the reaction scheme are known and can be prepared as described in European Patent Publication No. 314 435, the disclosure of which is incorporated herein by reference or It was described in detail.

In step 1 of the reaction scheme, a ring-open hydrolysis reaction is carried out to the lactone ring of the compound of the general formula (4) which is a known reaction, and then the product is esterified to obtain the compound of the general formula (2).

The lactone ring opening reaction is carried out by contacting with an alkali molar amount, preferably greater than the molar amount, with alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide. The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent used as long as it can dissolve the reagent at least to some extent without adversely affecting the reaction or reagents involved. Examples of suitable solvents include water; Alcohols such as methanol, ethanol, propanol or ethylene glycol; Ethers such as tetrahydrofuran; Or a mixture of one or more of said organic solvents with water.

The reaction can be carried out over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. It has been found to be convenient to carry out generally at 0-100 ° C., more preferably at about room temperature. The time required for the reaction can also be very wide depending on various factors, in particular the reaction temperature and the nature of the reagents and solvents used. However, as long as the reaction is carried out under the above-mentioned preferred conditions, generally 3 to 48 hours, more preferably 5 to 24 hours is sufficient.

The esterification step can be carried out by removing the solvent from the reaction mixture and then contacting the metal salt of the resulting carboxylic acid with a suitable active esterifying agent to the desired group R ^a , for example an alkyl halide, alkenyl halide or aralkyl halide. Can be. The reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent used so long as it can dissolve the reagent at least to some extent without adversely affecting the reaction or reagents involved. Examples of suitable solvents include amides, especially formamide compounds such as dimethylformamide; Ethers such as tetrahydrofuran; Dialkyl sulfoxides such as dimethyl sulfoxide; And ketones such as acetone. Alternatively, the metal salt of the resulting carboxylic acid is dissolved in an aqueous solvent and converted to the free carboxylic acid by addition of an inorganic acid (eg hydrochloric acid), followed by the use of the carboxylic acid in the form of an ethereal solution. It can be contacted with this preferred diazoalkane.

In step 2, the compound of formula 2 obtained as described in step 1 is converted into the ester compound corresponding to the invention of formula 3. The reaction can be carried out by contacting the compound of formula 3 with an oxidizing agent by conventional methods. Examples of suitable oxidizing agents include organically active halogen compounds such as N-bromoacetamide, N-chlorosuccinimide or N-bromophthalimide; Or dimethyl sulfoxide in combination with dicyclohexylcarbodiimide, dimethyl sulfoxide in combination with oxalyl chloride, dimethyl sulfoxide in combination with trifluoroacetic anhydride, pyridine and dimethyl sulfoxide in combination with anhydrous sulfuric acid, pyridinium chlorochromate, pyridinium There are oxidation systems such as silver carbonate combined with chromate or Celite filter aids.

When dimethyl sulfoxide combined with dicyclohexyl carbodiimide is used, an acid catalyst such as phosphoric acid or trifluoroacetic acid is also preferably used. When using dimethyl sulfoxide combined with oxalyl chloride, dimethyl sulfoxide combined with anhydrous trifluoroacetic acid or dimethyl sulfoxide combined with pyridine and sulfuric anhydride, the reaction is a basic catalyst such as tertiary alkylamine (e.g. triethylamine). It is preferable to carry out under.

The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent used, as long as the reagent can be dissolved to at least to some extent without adversely affecting the reaction or reagents involved, and the preferred solvent depends on the nature of the oxidizing system used. For example, where an organically active halogen compound is used, examples of suitable solvents are aqueous organic solvents such as aqueous alcohols (eg t-butanol), aqueous ketones (eg acetone) or aqueous amines (eg pyridine). Dimethyl sulfoxide in combination with dicyclohexylcarbodiimide, dimethyl sulfoxide in combination with oxalyl chloride, dimethyl sulfoxide in combination with anhydrous trifluoroacetic acid, dimethyl sulfoxide in combination with pyridine and anhydrous sulfuric acid, pyridinium chlorochromate, pyridinium di When using silver carbonate combined with chromate or celite, suitable solvents include, for example, sulfoxides such as dimethyl sulfoxide; Aromatic hydrocarbons such as benzene or toluene; And halogenated hydrocarbons, in particular halogenated aliphatic hydrocarbons such as methylene chloride or chloroform.

The reaction can be carried out over a wide range of temperatures and the exact reaction temperature is not critical to the present invention but the preferred temperature will depend on the nature of the oxidant used. Generally, when using dimethyl sulfoxide in combination with oxalyl chloride or dimethyl sulfoxide in combination with trifluoroacetic anhydride, it is preferable to carry out the reaction at -78 to 40 ° C, more preferably -50 to about room temperature. Convenient; When using silver carbonate combined with celite, suitable temperature is 0-100 degreeC, More preferably, it is room temperature-100 degreeC; When using other oxidizing agents, it turned out that the suitable temperature is 0-50 degreeC, More preferably, it is 10-30 degreeC. The time required for the reaction can also vary widely depending on various factors, in particular the reaction temperature and the nature of the reagents and solvents used. However, if the reaction is carried out under the above preferred conditions, generally 10 minutes to 12 hours will be sufficient.

After completion of the reaction, the desired compound can be collected from the reaction mixture by conventional methods. One example of a suitable recovery method includes adding an organic solvent that is not miscible with water to the reaction mixture to extract the desired compound; The organic layer is washed with water and the solvent is distilled off to give the desired compound. If desired, the desired compound can be further purified by conventional methods such as recrystallization, reprecipitation or various chromatographic methods, in particular column chromatography.

Step 3 is an optional step, to prepare a carboxylic acid of Formula 1 or a salt thereof.

The reaction to obtain the carboxylic acid is carried out by treating the ester compound of the formula (3) in a manner similar to step 1 described above to hydrolyze the lactone compound of the formula (4). For example, the reaction can be carried out by contacting an ester compound of formula 3 with at least equimolar amounts, preferably more than equimolar amounts of alkali, for example alkali metal compounds such as sodium hydroxide, potassium hydroxide or lithium hydroxide. The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent used as long as it can dissolve the reagent to at least some extent without adversely affecting the reaction or reagents involved. Examples of suitable solvents include water; Alcohols such as methanol, ethanol, propanol or ethylene glycol; Ethers such as tetrahydrofuran or dioxane; Or a mixture of one or more of said organic solvents with water.

The reaction can be carried out over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. It has been found to be convenient to carry out generally at 0-100 ° C., more preferably at about room temperature. The time required for the reaction can also vary widely depending on various factors, in particular the reaction temperature and the nature of the reagents and solvents used. However, if the reaction is carried out under the above preferred conditions, generally 3 to 48 hours, more preferably 5 to 24 hours is sufficient.

After the reaction is completed, the reaction solution is made acidic by adding an inorganic acid (eg hydrochloric acid). The free carboxylic acid can then be extracted by adding an organic solvent that is not miscible with water. The extract is then washed with water and the solvent removed to give the desired carboxylic acid from the extract. If desired, the desired carboxylic acid can be further purified by conventional methods such as recrystallization, reprecipitation or various chromatographic methods, in particular column chromatography.

Alternatively, the carboxylic acid of formula (1) may be prepared by reacting an ester compound of formula (3), in which R ^a represents an alkenyl group, with a proton donor in the presence of ^a palladium complex in an inert solvent. Such reactions are currently known and the reagents used may be those used for known reactions of this kind. For example, suitable palladium complexes that may be used are complexes in which zero-valent palladium is coordinated with an organophosphorus compound such as triphenylphosphine, tributylphosphine or triethyl phosphite, preferably tetrakis (triphenylphosphine). Palladium (0).

Examples of suitable proton donors include organic carboxylic acids such as formic acid, acetic acid or benzoic acid; Phenols such as phenol or cresol; And active methylene compounds such as diethyl malonate or ethyl acetoacetate. Among these, organic carboxylic acids are preferable.

The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent used as long as it can dissolve the reagent to at least some extent without adversely affecting the reaction or reagents involved. Examples of suitable solvents include hydrocarbons containing aliphatic and aromatic hydrocarbons, such as hexane or benzene; Halogenated hydrocarbons, in particular halogenated aliphatic hydrocarbons such as methylene chloride or chloroform; Ethers such as diethyl ether, tetrahydrofuran or dioxane; Alcohols such as methanol, ethanol or t-butanol; Ketones such as acetone or methylethyl ketone; Esters such as methyl acetate or ethyl acetate; Amides such as dimethylformamide or dimethylacetamide; And sulfoxides such as dimethyl sulfoxide. Of these, ether is preferred. The solvents may be used alone or in a mixture of two or more.

The reaction is preferably carried out in the absence of oxygen, for example in a stream of nitrogen. The reaction can be carried out over a wide range of temperatures and the exact reaction temperature is not critical to the invention. In general, it is convenient to carry out the reaction at 0 to 40 ° C. The time required for the reaction can also vary widely depending on various factors, in particular the reaction temperature and the nature of the reagents and solvents used. However, as long as the reaction is carried out under the above-mentioned preferred conditions, generally 30 minutes to 24 hours is sufficient. The reaction is preferably carried out under stirring or by standing the reaction mixture.

After completion of the reaction, the desired compound obtained in each reaction can be recovered from the reaction mixture by conventional methods. One example of a suitable recovery method is cooling the reaction solution and separating the crystals obtained by filtration; Or the insoluble matter is removed by filtration, water is added, and the mixture is extracted with an organic solvent that is not miscible with water; Or water is added and the aqueous layer is acidified and the mixture is extracted with an organic solvent that is not miscible with water. The resulting compound can be further purified by recrystallization, reprecipitation or various chromatographic methods, in particular column chromatography, if necessary.

In addition, the carboxylic acid of formula (1) can be prepared by catalytic reduction of an ester compound of formula (3) in which R ^a represents an aralkyl group in the presence of hydrogen. As for the pressure of hydrogen used, 1-5 atmospheres are preferable.

Examples of suitable catalysts that can be used are palladium / carbon, platinum oxide and rannickel, of which palladium / carbon is preferred.

The reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent used as long as it can dissolve at least to some extent without adversely affecting the reaction or reagents involved. Examples of suitable solvents include alcohols such as methanol or ethanol; Ethers such as diethyl ether, tetrahydrofuran or dioxane; Amides such as dimethylformamide or dimethylacetamide; And aqueous organic solvents which are, for example, aqueous organic carboxylic acids such as aqueous formic acid or aqueous acetic acid. Of these, preference is given to using aqueous organic acids or alcohols. The reaction can be carried out over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. In general, it has been found to be convenient to carry out the reaction at 0 to 50 ° C, more preferably at about room temperature 0 to 40 ° C. The time required for the reaction can also vary widely depending on various factors, in particular the reaction temperature and the nature of the reagents and solvents used. However, as long as the reaction is carried out under the above-mentioned preferred conditions, generally 1 to 6 hours is sufficient.

After completion of the reaction, the reaction mixture can be filtered to remove the catalyst, followed by removal of the solvent, for example by distillation, to obtain the desired compound. If desired, the resultant compound can be further purified by conventional methods such as recrystallization, reprecipitation or various chromatographic methods, in particular column chromatography.

The metal salt of the carboxylic acid of formula (1) may be mixed with a metal hydroxide or metal carbonate to prepare the salt, such as sodium hydroxide, potassium hydroxide, calcium hydroxide or sodium carbonate, in a suitable aqueous organic solvent such as water or aqueous alcohol, aqueous acetone or aqueous dioxane. It can be prepared by contacting carboxylic acid. The amount of the metal compound is not important, but in order to minimize the waste of the carboxylic acid, it is preferable to use it in an equimolar amount or more with respect to the carboxylic acid. Generally, it is preferable to use 1-1.5 mol of metal hydroxides or metal carbonates per mol of carboxylic acids.

After terminating the reaction, the desired compound can be obtained from the reaction mixture by conventional methods. For example, the desired compound can be recovered from the reaction mixture by distilling off the solvent under reduced pressure and then freeze drying the mixture. The resulting compound can be further purified by conventional methods such as recrystallization, reprecipitation or various chromatographic methods, preferably column chromatography, if necessary.

As described above, the compounds of the formula (4) used as starting materials in the above reaction scheme are known and are disclosed in Japanese Patent Application Laid-Open Nos. 58-55443 (European Patent Publication No. 76601) and Japanese Patent Application Laid-Open No. Hei 2-255. (European Patent Publication No. 314 435) and can be prepared according to the methods described in these patents. Starting materials ML-236B, MB-530B, M-4 and M-4 ′ which can be used in the preparation of the compound of formula 4 are also disclosed in Japanese Patent Application Laid-Open No. 58-55443 and Japanese Patent Application Laid-Open No. Hei 2-255. Although described, it may also be obtained by culturing the following microorganisms.

An example of a strain of microorganisms capable of producing ML-236B is Penicillium citrinum Thom (SANK 13380) belonging to the genus Penicillium. It was deposited on 22 December 1992 under the accession number FERM BP-4129 under the Budapest Treaty. The bacteriological properties of strain SANK 13380 are as follows:

Colonies on Czapek yeast autolysate agar (CYA) media were 1.8 cm in diameter after growth at 25 ° C. for 7 days. The surface color was white (1A1) to pale yellow (2A4) and the surface was covered with white woolly parasitic mycelium. Back side was white (1A1) to pale yellow (2A4) and radial wrinkles were observed. No exudate or soluble pigment was found.

Colonies on the malt extract agar (MEA) medium were 1.3 cm in diameter (after propagation at 25 ° C. for 7 days). The surface was pale yellow (2A3) and the surface appearance changed from velvet to powdery. The back side is colored brownish orange (7C7).

Colonies on 25% w / vglycerol nitrate agar (G25N) media were 1.6 cm in diameter (after 7 days propagation at 25 ° C). The surface color ranged from white (1Al) to yellowish white (1A2) and the surface was covered with woolly hyphae. The backside is colored in pale yellow (2A3).

No proliferation was observed at 5 ° C. or 37 ° C. in any of these media.

The surface of Condiodiopor is flat and double-biotic. Metulae is a slightly vesicular, 9-15 × 3-4 μm cylindrical. Pialides are in the form of only 8-10 × 3-4 μm in size. Condydia is a spherical diameter of 2.5-4 μm and the surface is a slightly rough flat surface.

Comparing these properties with those of known species, the properties of this strain are described in penicillium citrium as described in JI Pitt in The genus Penicillium and its telemorpholic states, Eupenicillium and Talaromyces, p634, Academic Press (1979). It was found to be consistent with the properties of Tom (Penicillim citrinum Thom). Thus, this strain has been identified as penicillium citrinum tom.

The description of hue follows the guidelines of A. Kornerup and H. H. Wansher in Methuen Handbook of Color, 3rd Ed. (1978) Published by Eyre Methuen (London).

It will be appreciated that certain other strains capable of producing SANK 13380, or ML-236B, can be subcultured, biotechnically replaced or altered to produce organisms with other properties. The only requirement is that the organism obtained can produce the desired compound. Changes can be caused, for example, by ultraviolet radiation, radio frequency radiation, and chemical mutagens to occur naturally or artificially.

Such alterations and modifications may be achieved in any desired form or will depend on considerations such as, for example, culture conditions. Strains may be altered by culture and may be selected to exhibit characteristics such as high growth or to grow at lower / higher temperatures.

Biotechnological alterations will generally be intentional and sometimes introduce selectable properties such as bacteria resistance or susceptibility or combinations thereof to maintain purity or to allow for the purification of cultures, particularly seed cultures.

Genetic engineering suggests that other properties that may be introduced are acceptable for penicillium spp. For example, plasmids that confer resistance can be incorporated or naturally occurring plasmids can be removed. Advantageous plasmids include those that confer oxotropy. The plasmid may be obtained from a suitable source or may be manipulated to isolate naturally occurring penicillium plasmids and to insert genes obtained from a desired gene or other source. Natural plasmids may also be altered in certain other ways that may be considered desirable.

Such modified strains can be used in the method of the present invention as long as they can produce ML-236B, and production can be easily confirmed by simple and routine experimentation.

In order to obtain ML-236B from a culture of suitable microorganisms, the microorganisms must be fermented in a suitable medium. Such media are generally known in the art and will often be in the form commonly used in the production of other fermentation products.

Typically, the medium needs to contain a combination of carbon source, nitrogen source and one or more inorganic salts that can be absorbed by the associated microorganism. The minimum requirement for the medium will be to contain the ingredients necessary for the growth of microorganisms.

Suitable carbon sources include carbon-containing substances which can be absorbed by microorganisms, for example carbohydrates such as glucose, fructose, maltose, lactose, sucrose, starch, mannitol, dextrin, glycerin, dark malt syrup, molasses Blackstrap molasses, oat powder, rye powder, corn starch, potatoes, corn powder, soybean powder or malt extract; Fats and oils such as soy milk, cottonseed oil, olive oil, cod liver oil or lard oil; Organic acids such as citric acid, sodium ascorbate, malic acid, acetic acid, fumaric acid, tartaric acid, succinic acid or gluconic acid; Alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, or t-butanol; And amino acids such as glutamic acid. These materials may be used alone or a mixture of two or more of these materials may be used. Typical amounts can range from about 1 to 10% w / v of the amount of medium, but this amount can vary depending on the desired result.

Suitable nitrogen sources include nitrogen containing materials that can be absorbed by microorganisms, for example, materials containing proteins or other materials that can readily absorb nitrogen sources. Representative examples of nitrogen sources include coarse soy flour, bran, wheat germ, coarse peanut powder, coarse cottonseed flour, cottonseed oil, soy protein isolate, casamino acid, casein hydrolyzate, fermamine, coarse fish flour, corn impregnation, peptone, grain extract Organic nitrogen sources from animals and plants that can be extracted from natural sources such as yeast, yeast autolysates, yeast extracts, malt extracts and urea; Amino acids such as aspartic acid, glutamine, cystine or alanine; Ammonium salts such as ammonium sulfate, ammonium nitrate, ammonium chloride or ammonium phosphate; And inorganic nitrogen compounds such as sodium nitrate or potassium nitrate. As in the case of carbon sources, they can be used alone or in combination. Suitable amounts are generally in the range of about 0.2-6% w / v of the amount of medium.

Nutritious suitable inorganic salts are those that provide the trace elements as well as the major constituents of the salts. Preferably, the salts should provide in traceable form trace metals such as sodium, potassium, magnesium, ammonium, calcium, phosphate, sulfate, chloride or carbonate, preferably molybdenum, boron, copper, cobalt, manganese and iron. . Examples of suitable compounds include sodium chloride, manganese chloride, cobalt chloride, calcium chloride, calcium chloride, calcium carbonate, potassium aluminum sulfate, manganese sulfate, cupric sulfate, cobalt sulfate, zinc sulfate, ferrous sulfate, magnesium sulfate, monophosphate Potassium, dipotassium phosphate, disodium phosphate, or ammonium molybdate. In addition, other additives necessary to promote the growth of microorganisms and the formation of ML-236B can also be used as suitable combinations.

The addition of sulfur compounds that can be absorbed by the microorganisms from the medium can often increase the productivity of the desired compound. Suitable sulfur compounds include sulfates such as zinc sulfate, ferrous sulfate, cupric sulfate or ammonium sulfate; Thiosulfates such as ammonium thiosulfate; And sulfites such as ammonium sulfite; Or sulfur-containing amino acids such as cysteine, cystine, or L-thiazoline-4-carboxylic acid; Heavy metal sulfate compounds such as ferrous sulfate or cupric sulfate; Vitamins such as vitamin B ₁ or biotin; And organosulfur compounds comprising bacterial growth promoting factors such as thiamine.

Foam inhibitors such as silicone oils, polyalkylene glycol ethers, vegetable oils, or suitable surfactants may be added to the medium. Such addition will be particularly suitable if the microorganism is fermented in the culture.

When used for the production of ML-236B, the pH of the culture medium (or medium) for the cultivation of penicillium citrineum tom SANK 13380 should be maintained in the pH 5.0 to 8.0 range, more preferably in the pH 6.0 to 7.0 range. However, the only requirement is that pH should not interfere with the growth of microorganisms or irreversibly adversely affect the quality of the final product.

Penicillium citium tom SANK 13380 generally grows at temperatures ranging from 15 ° C. to 35 ° C. and grows well at 22 ° C. to 30 ° C. Other temperatures outside this range may also be applied when developing strains capable of growing at lower or higher temperatures or for other special purposes, as is well known in the art. For the production of ML-236B, the preferred temperature is 22 ° C. to 26 ° C., more preferably about 24 ° C.

The culture technique used for the production of ML-236B is not specific, and the culture method commonly used for bacterial growth can be used equally here. However, ML-236B is ideally obtained by aerobic culture, and suitable aerobic culture techniques such as solid culture method, stirred culture method, stop culture method, shake culture method, or aeration-stirred culture method can be used.

When culturing is carried out on a small scale, shaking cultures fermented for several days at 20 to 30 ° C, preferably about 24 ° C, are generally preferred.

To start the fermentational cultivation, the preferred technique uses an initial inoculum prepared in one or two stages, preferably in an Erlenmeyer flask, preferably provided with a pear pool (water flow control wall). Carbon and nitrogen sources can be used in the formulation for culture. The seed flask is allowed to have a suitable temperature for a suitable period of time, usually 2 to 7 days, or until sufficient growth is observed, preferably for 3 to 5 days, for example 22 to 26 ° C, more preferably about 24 ° C. In, shake in a constant temperature incubator. The seed culture obtained can then be used to inoculate the second seed culture or the resulting culture. In the case of a second inoculation, this can be done in a similar manner and used in part to inoculate the production medium. The flasks inoculated with seed culture are shaken at a suitable temperature, for example at 24 ° C., for a suitable period of time, for example 2 to 7 days, or until maximum productivity is obtained. Once the inoculation is complete, the contents in the flask can be collected by centrifugation or filtration.

If the cultivation is carried out on a large scale, cultivation in a suitable breathable-stirred fermenter would be preferred. In this process, nutrient media can be prepared in the fermentor. The medium is first sterilized at a suitable high temperature, for example at about 120 ° C., then cooled and inoculated with the inoculum already grown on the sterile medium. Cultivation is preferably carried out at a temperature of 20 to 26 ° C, preferably at 22 to 24 ° C with stirring and aeration. This procedure is suitable for obtaining large amounts of compounds.

The amount of ML-236B produced by incubation over time can be retrieved, for example, by sampling and evaluating the amount of ML-236B with high performance liquid chromatography. ML-236B can exist in both lactone and hydroxy forms and will usually be produced as a mixture of these forms. At the same time, the amount of each form can be determined. In general, the amount of ML-236B produced reaches a maximum after a period ranging from 72 hours to 300 hours.

ML-236B produced by the culture is present both in the culture filtrate and in bacterial cells. ML-236B may be in hydroxy-acid form or in lactone form, each of which may vary in different forms. In addition, the hydroxy-acid form can form the corresponding salt, which will be stable.

Thus, ML-236B can be extracted or collected directly using these properties, along with other properties, for example as follows.

[Method 1]

Bacterial cells and other solids in the medium are filtered or centrifuged using filter aids such as diatomaceous earth to separate the supernatants and bacterial cells.

(1) Supernatant

The lactone ring in the lactone form of the ML-236B molecule present in the supernatant is hydrolyzed under alkaline conditions (preferably above pH 12) so that it is ring-opened and everything in ML-236B is converted to the hydroxy-acid form. This salt is then converted to the corresponding free hydroxy-acid by careful acidification. ML-236B is then a water-insoluble organic solvent such as aliphatic hydrocarbons such as hexane or heptane; Aromatic hydrocarbons such as benzene, toluene or xylene; Methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene and eggs are halogenated hydrocarbons; Ethers such as diethyl ether or diisopropyl ether; Extracted with esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate is obtained from this mixture as freehydroxy-acid. One or a mixture of two or more of these solvents may be used.

(2) bacteria cells

Bacterial cells may be water-soluble organic solvents such as alcohols such as methanol or ethanol; Ketones such as acetone; Nitriles such as acetonitrile or isobutyronitrile; Mixed with amides such as dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphor triamide. The final concentration of the bacterial cells in the mixture obtained is preferably 50 to 90%. The resulting mixture is preferably treated in the same manner as in the case of the supernatant described above to obtain free hydroxy acid.

[Method 2]

The medium is heated in an alkaline state (preferably at pH 12 or above) or treated at room temperature to destroy the cells, and then hydrolyzed to ring-open the lactone ring in the molecule. At this time, both ML-236B are converted to its hydroxy-acid salt form. Treatment similar to that described above for the supernatant of Method 1 yields ML-236B in free hydroxy acid form after the salt form is converted to the corresponding free hydroxy acid form.

The resulting free hydroxy acid form may be dissolved in the form of a salt in an aqueous alkali metal base solution, for example an alkali metal hydroxide such as sodium hydroxide. Moreover, the free hydroxy acid form can be readily obtained and converted to the most stable salts.

Alternatively, the obtained free hydroxy acid form can be dehydrated by heating or closed in its organic solvent and converted to its lactone form.

Isolation and purification in the form of free hydroxy acids, hydroxy acid salts and lactones thus obtained can be carried out by conventional means usually used for the isolation and purification of organic compounds. Examples of such methods include methods using synthetic adsorbents, such as carriers, Sephadex LH-20 (tradename of Pharmacia), Amberlite XAD-11 (tradename of Rohm and Haas) or Diion HP-20 (Mitsubishi Chem). Distribution chromatography using Ind. Alternatively, it can be isolated and purified using normal or reversed phase column chromatography (preferably high performance liquid chromatography) using silica gel or alkylated silica gel and eluted with a suitable solvent.

The lactone forms can also be purified by adsorption column chromatography using carriers such as silica gel, alumina or florisil (trade name for carriers in the form of magnesium-silica gel).

Examples of solvents that can be used as the eluent include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; And ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether.

Alternatively, the extract is passed through a column using an adsorbent to remove impurities; Or by adsorbing a free hydroxy acid form on such a column and then eluting with an aqueous alcohol such as aqueous methanol, aqueous ethanol, aqueous butanol or aqueous isopropanol, or an aqueous ketone such as aqueous acetone. . Suitable adsorbents used include activated carbon, or Amberlite XASD-2, XAD-2 (tradename of Rohm Haas) or Diaion HP-10, HP-20, CHP-20, HP-50 (Mitsubishi Chemical Industries, Ltd.) Adsorption resins).

The free hydroxy acids and salts of hydroxy acids can be converted to the other compounds respectively by conventional methods and purified in any desired form.

In addition, ML-236B can be produced chemically by the method described in the literature.

Microorganisms capable of producing MB-530B include, for example, Monascus ruber van Tieghem SANK 15679 belonging to the genus Monascus. This strain was deposited under the terms of the Budapest Treaty to the Institute of Commerce, Industry, and Technology, Institute of Bioscience and Technology (formerly known as the Institute of Industrial Technology, Microbial Industry and Technology), of the Ministry of International Commerce and Industry located in Tokyo, Japan; FREM BP-4246, Deposited Day; Deposited March 24, 1993. Monascus louver teeeghem SANM 15679 has already been deposited internationally as number 2 because it is already described as Monascus louver 1005 in British Patent No. 2046737 and deposited internationally as FERM BP-682. Its bacteriological properties and cultivation method are the same as described in the above British patent.

M-4 and M-4 'can be obtained by enzymatic stereospecific hydroxylation at position 6 of ML-236B. An example of a microorganism capable of converting ML-236B to M-4 by a hydroxylation reaction is Amycolate autotrophica SANK 62981, belonging to the genus Amycolata. This strain was deposited under the terms of the Budapest Treaty to the Ministry of Commerce, Industry and Energy of the Japan Institute of Commerce, Industry and Technology, Microbiological Technology Institute; FERM BP-4105, Deposited Date; Deposited internationally on 8 December 1992.

An example of a microorganism capable of converting ML-236B to M-4 ′ by a hydroxylation reaction is Syncephalastrum nigricans Vuillemin SANK 42372, which belongs to the genus Cefelasturum. This strain was deposited with the Ministry of Trade, Industry and Energy, Japan Institute of Microbiological Technology, under the conditions of the Budapest Treaty; FERM BP-4106, Deposited Date; Deposited internationally on 8 December 1992.

The bacteriological properties of this strain are as follows.

[Bacterial Properties of Amycollata Autotrophica SANK 62981]

Shirring and Gottlieb (International Journal of Systematic Bacteriology 16, 313-340 (1968)) and S. et al. a. According to the method of The Actinomycetes, this strain was observed for 14 days.

(1) Morphological characteristics

(2) Characteristics of various types of media for classification

This strain grows well in all media tested. Strain SANK 62981 grows from brownish white to pale yellow orange. As the culture progresses, brownish purple spots are observed.

Yeast Extract-Malt Extract The insertion of light gray aerial hyphae on a medium other than agar medium is observed.

No formation of soluble pigment is observed

In Table 2, G, AM, R, and SP mean growth, aerial mycelium, reverse and soluble pigment, respectively.

The color tone in Table 2 was indicated according to the color tip number described in [Standard Color Table] issued by Nippon Shikisai Genjojo.

(3) physiological characteristics

(4) assimilation of various carbon sources

The assimilation capacity of the carbon source was investigated using Friedham-Gottlieb agar medium (ISP 9) and determined after incubation at 28 ° C. for 14 days.

(5) intracellular components

ratio. Becker et al., Applied Microbiology, 12, 236, (1965) and M. et al. blood. Acid hydrolysates of this strain cell were analyzed by paper chromatography, according to the method of Lecevalier et al., The Actinomycetales by H. Prauser, p 311 (1970). Meso-2, 6-diaminopimelic acid was observed in the cell wall, and arabinose and galactose were shown as sugar components of bacterial cells, which confirmed that the bacterial components were type IV-A.

Mycolic acid was not observed.

From this result, strain SANK 62981 was determined to belong to the Amikolata autotrophica species.

However, SANK 62981 shows amethystine hue after propagation, and thus may be a subspecies of amicollata autotrophica.

This strain was deposited under the terms of the Budapest Treaty to the Japan Institute of Commerce, Industry, and Energy and the Institute of Microbiological Technology. Deposited as FERM BP-4105.

This strain is the basis of the International Streptomyces Project; [Berjay's Guide to Determination of Bacteriology, 8th Edition]; s. a. The Actinomycetes, Vol. 2; and the recent report on Actinomycetes. Up until now, the Amicollata genus has been classified as part of the genus Nocardia. Because of the differences, amikolata is now regarded as a genus independent from Nocardia, each forming a new genus [International Journal of Systematic Bacteriology, 36, 29 (1986)].

[Bacterial Properties of Syncephalum nigrican's Bulemin SANK 42372]

Asexual mycelia develop very well and grow rapidly. Spore sac vertically upright from mycelium is pale brown, with septum and irregular branches, forming a septum. The side branches sometimes bend rapidly.

Vesicles form at the top of the main axis and side branches. The vesicles are slightly spherical or eggs, sometimes ellipsoidal, the ones formed on the top of the main axis having a diameter of 28 μm to 50 μm, and the ones formed on the top of the side branches from 15 μm to 25 μm in diameter.

Many segmental follicles form on the anterior surface. Spore cysts are single rod-shaped or finger-shaped, with mainly 5 to 10 spores formed in a row.

Spores are mostly unicellular, slightly spherical to oval, and colorless on smooth surfaces, 3.5 to 6.5 μm in diameter.

Junction spores are not observed.

Comparing the characteristics of the known strains with those of the strains, the characteristics of the strains were Keisuke Suvaki and Sunichi Udagawa, written by Godansa An Illustrated Book of Fungi; It is in good agreement with the syncephalum nigricans bulemin described in p 303-304 (1978).

This strain has been deposited with the Accession No. FERM BP-4106 under the terms of the Budapest Treaty to the Ministry of Commerce, Industry and Technology Microbiological Industry and Technology Institute of the Ministry of Commerce, Industry and Energy.

This microorganism is cultured on a medium containing nutrients that can be assimilated by this microorganism under culture conditions suitable for growth of the converting microorganism, and then treated according to any of the following methods, for example, ML −. It can be used to introduce a hydroxyl group at the 6-position of 236B.

[Method 1]

At the intermediate stage of incubation of the converting microorganism, the starting compound, for example ML-236B, is added to the medium and contacted with the microorganisms during subsequent incubation.

[Method 2]

Cultivate and collect the converting microorganisms. The cells obtained are then contacted with the starting compound.

[Method 3]

Cell-free extracts containing active enzymes are prepared from the cells of the converting microorganism and the cell-free extracts are contacted with the starting compound.

Examples of medium containing nutrients assimilable by the converting microorganism, general culture methods, pH of the medium suitable for the growth of the converting microorganism, temperature and isolation and purification conditions of the medium suitable for the growth of the converting microorganism are described in the preparation of ML-236B. All are the same as described above.

The above-mentioned strains, or any other strains with similar activity, may be preferably sub-cultured or biotechnically altered or modified to produce organisms with other properties. The only requirement is that the resulting organisms be able to produce the required compounds. Alternatively, the change may occur naturally or artificially.

Such changes and modifications may be in any desired form or may result in consideration of considerations such as, for example, culture conditions. Strains can be modified by culturing and can be chosen to exhibit properties such as improved proliferation or proliferation at low / high temperatures.

Biotechnological modifications are generally intentional and may introduce optional properties such as sometimes bacteriostatic or susceptible, or a combination thereof, for maintaining purity or for purification of cultures, particularly species cultures.

Other properties that can be introduced by genetic engineering are any acceptable in the species of the strain. For example, the plasmid encoding the resistance may be inoculated or the plasmid naturally occurring may be removed. Advantageous plasmids include those that impart trophic composition. Plasmids may be obtained from suitable sources, or may be engineered by isolating naturally occurring plasmids and inserting the desired gene (s) from other sources. In addition, natural plasmids can be modified in any other way that may be considered desirable.

Any of the above modified strains can be used in the method of the present invention as long as they can have the required activity which can be easily identified by simple and routine experiments.

[Biological activity]

Compounds of the present invention have a significant ability to reduce serum cholesterol levels. In particular, this compound inhibits by synthesizing 3 -hydroxy-3 -methylglutaryl -CoA reductase (HMG-CoA), a rate limiting enzyme of cholesterol biosynthesis, by enzymatic system or culture isolated from experimental animals. It inhibits cholesterol biosynthesis in the cell system. This suggests that the compounds of the present invention show potent serum cholesterol inhibitory effects when used in the treatment of humans or other animals. Determination of the inhibitory activity of the compounds of the present invention has several improvements. second. Known methods such as Shapiro et al. [Analytical Biochemistry Vol. 31, pp. 383 390 (1969)], Kuroda et al., Biochimica et Biophysica Acta Vol. 486, pp. 70 to 81 (1977).

The results are shown in Table 3.

In Table 3, all of the compounds of the present invention have better activity than their directly comparable hydroxy equivalents, and in compounds 6 * and 7 * obtained by oxidation of the hydroxyl groups at the 5-positions of compounds 4 * and 5 *, respectively , Activity is much lower than the original hydroxy compound. On the other hand, in the 5-oxo compound in the octahydronaphthalene-substituted oxime derivative of the present invention, the activity is higher than the original hydroxy compound.

Compounds of the present invention inhibit cholesterol synthesis and serve to reduce lipid levels in the blood. Thus, the compound can be used for treatment as a blood fat reducing agent or as a preventive agent for the pulmonary dystrophy.

The compound may be administered orally or parenterally, for example in capsules, tablets, injections, or other conventional dosage forms. The dosage of the compound depends not only on the age, condition and weight of the patient, but also on the nature and severity of the symptoms, but generally in adult patients 0.5 mg to 500 mg per day, or divided doses, ie It is suggested to administer two to four doses per day. However, if desired, an amount above this range can be administered.

The compounds of the present invention are preferably administered in conventional pharmaceutical formulations mixed with one or more conventional excipients, carriers or diluents as are well known for compounds having this type of activity.

The invention is further illustrated by the following examples which show preparation examples of the compounds of the invention. Successive preparations illustrate the preparation of certain starting materials used in the preparation of the compounds of the invention.

182 μl (1.3 mmole) of trifluoroacetic anhydride is dissolved in 2 ml of anhydrous toluene and the resulting solution is cooled to −78 ° C. Then 1 ml of anhydrous toluene in which 121 μl (1.71 nmole) of dimethyl sulfoxide is dissolved is added dropwise to the cooled solution over 5 minutes under a nitrogen atmosphere. After completion of the dropwise addition, the mixed solution was stirred for 3 minutes, and then 500 mg (0.86 nmole) of allyl 7-[5-benzyloxyimino-2 -methyl-8-(2-methylbutyryloxy) -3 -oxo-1, 2, 3, 5, 6, 7, 8, 8a-octahydro-1 naphthyl] 3 ml of anhydrous toluene in which 3, 5-dihydroxyheptanoate (prepared as described in Preparation Example 1) was dissolved Add dropwise over 15 minutes. The solution is stirred at −78 ° C. for 15 minutes, followed by dropwise addition of 0.6 ml (4.3 mmole) of triethylamine over 5 minutes. The obtained reaction mixture is stirred at -78 ° C for 20 minutes and further at 0 ° C for 40 minutes. Thereafter, 50 ml of an aqueous 10% w / v citric acid solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate at room temperature. The ethyl acetate extract is washed with saturated aqueous sodium hydrogen carbonate solution followed by saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. The oil residue obtained was purified by silica gel flash column chromatography using a 2: 1 volume mixture of ethyl acetate and hexane as eluent to afford 183 mg (48% yield) of the title compound. At this time, 166 mg of unreacted starting material is also recovered.

239 mg (0.4 mmole) of allyl 7- [5-benzyloxyimino-2-methyl-8- (2-methylbutyryloxy) -3-oxo-1,2,3,5 in 3.3 ml of anhydrous tetrahydrofuran. , 6, 7, 8, 8a-octahydro-1-naphthyl]-3-hydroxy-5-oxoheptanoate (prepared as described in Example la), 20.7 mg (0.02 mmole) Tetrakis (triphenylphosphine) palladium (0), 21.5 mg (0.08 mmole) of triphenylphosphine and 31 μl (0.82 mmole) of formic acid were added to the solution, and the resulting mixture was stirred for 18 hours under a nitrogen atmosphere. do. After stirring, the reaction mixture is concentrated by evaporation under reduced pressure and the residue is dissolved in 50% v / v acetonitrile aqueous solution. The solution is filtered through SEP-PAK C-18 Cartridge (trade name of Waters Co.) and extracted with ethyl acetate. The ethyl acetate extract obtained is concentrated over anhydrous magnesium sulfate by drying, filtration and evaporation under reduced pressure. The obtained oily residue was subjected to a reverse phase Lobar column (RP-18) using a buffer (pH 3.0) consisting of a 1: 1 volume mixture of aqueous phosphoric acid and acetonitrile containing 0.001 M triethylamine as eluent. Purification by Size B, Merck) yields 106 mg (48% yield) of the title compound as an oily substance.

103 mg of 7- [5-benzyloxyimino-2-methyl-8- (2-methylbutyryloxy) -3-oxo-1,2,3,5,6 in 2 ml of a 1: 1 volume mixture of dioxane and water , 7, 8, 8a-octahydro-1-naphthyl] -3-hydroxy-5-oxoheptanoic acid (prepared as described in Example 1b) is dissolved. Then, 1.8 ml of 0.1 N aqueous sodium hydroxide solution was added dropwise to the solution at 0 ° C. over 5 minutes, and then the solution was stirred at room temperature for 1 hour. After stirring, the solution is lyophilized to yield 107 mg of the title compound as a colorless powder that is sensitive to wetting.

1.33 g of allyl 7- [5-(furan-2-yl) methoxyimino-2--2-methyl-8- (2-methylbutyryloxy) -3-oxo-1, 2, 3, 5, 6, 7 , 8, 8a-octahydro-1-naphthyl] -3, 5-dihydroxyheptanoate (prepared as described in Preparation Example 2), except that a method similar to that described in Example 1a was used. Repeat to give 599 mg of the title compound.

490 mg of allyl 7- [5-(furan-2-yl) methoxyimino-2--2-methyl-8- (2-methylbutyryloxy) -3-oxo-1, 2, 3, 5, 6, 7, 8, 8a-octahydro-1-naphthyl] -3-hydroxy-5-oxoheptanoate (prepared as described in Example 2a), but with a similar method as described in Example 1b Repeating to give 329 mg of the title compound.

10.6 g of allyl 7- [5- (1,3-dioxane-5-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3-oxo-1, 2, 3, 5, 6, 7, 8, 8a-octahydro-1-naphthyl] -3, 5-dihydroxyheptanoate (prepared as described in Preparation Example 3) except that in Example 1a Repeat in a similar manner as described to yield 4.3 g of the title compound.

4.9 g of allyl 7- [5- (1,3-dioxane-5-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3-oxo-1, 2, 3, Example 1b, except that 5, 6, 7, 8, 8a-octahydro-1-naphthyl] -3hydroxy-5-oxoheptanoate (prepared as described in Example 3a) is used Repeat in a similar manner as described for yielding 3.1 g of the title compound.

670 mg of allyl 7- [5- (2-ethoxybenzyloxyimino) -2-methyl-8- (2-methylbutyryloxy) -3-oxo-1, 2, 3, 5, 6, 7, 8 , 8a-octahydro-1-naphthyl] -3,5-dihydroxyheptanoate (prepared as described in Preparation Example 4), except that it is repeated in a similar manner as described in Example la To give 205 mg of the title compound.

191 mg allyl 7- [5- (2-ethoxybenzyloxyimino) -2-methyl-8- (2-methylbutyryloxy) -3-oxo-1, 2, 3, 5, 6, 7, 8 In a similar manner as described in Example 1b, except that 8a-octahydro-1-naphthyl] -3hydroxy-5oxoheptanoate (prepared as described in Example 4a) is used. Repeat, 164 mg of the title compound are obtained.

960 mg of allyl 7- [5- (2-chlorobenzyloxyimino) -2-methyl-8- (2-methylbutyryloxy) -3-oxo-1, 2, 3, 5, 6, 7, 8, 8a-octahydro-1-naphthyl] -3,5-dihydroxyheptanoate (prepared as described in Preparation Example 5), except that it was repeated in a similar manner as described in Example la 334 mg of the title compound are obtained.

289 mg of allyl 7- [5- (2-chlorobenzyloxyimino) -2-methyl-8- (2-methylbutyryloxy) -3-oxo-1, 2, 3, 5, 6, 7, 8, Repeated in a similar manner as described in Example 1b, except that 8a-octahydro-1-naphthyl] -3-hydroxy-5-oxoheptanoate (prepared as described in Example 5a) is used. This gives 209 mg of the title compound.

1.32 g of allyl 7- [5- (2,6-dichlorobenzyloxyimino) -2-methyl-8- (2-methylbutyryloxy) -3-oxo-1, 2, 3, 5, 6, 7 , 8, 8a-octahydro-1-naphthyl] -3, 5-dihydroxyheptanoate (prepared as described in Preparation Example 6), except that a method similar to that described in Example la was used. Repeat to give 481 mg of the title compound.

465 mg of allyl 7- [5- (2,6-chlorobenzyloxyimino) -2-methyl-8- (2-methylbutyryloxy) -3-oxo-1, 2, 3, 5, 6, 7, 8, 8a-octahydro-1-naphthyl] -3-hydroxy-5-oxoheptanoate (prepared as described in Example 6a), except that a method similar to that described in Example Ib is used. Repeating to give 339 mg of the title compound.

727 mg of allyl 7- [5- (3-methylisoxazol-5-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3-oxo-1, 2, 3, 5 , 6, 7, 8, 8a-octahydro-1-naphthyl] -3,5-dihydroxyheptanoate (prepared as described in Preparation Example 7) except that it is described in Example la Repeat in a similar manner to one to yield 298 mg of the title compound.

285 mg of allyl 7- [5- (3-methylisoxazol-5-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3 oxo-1,2,3,5 In Example 1b, except that 6, 7, 8, 8a-octahydro-1-naphthyl] -3-hydroxy-5oxoheptanoate (prepared as described in Example 7a) is used. Repeat in a similar manner as described to give 148 mg of the title compound.

1.27 g of allyl 7- [5- (2-thienyl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3-oxo-1,2,3,5,6,7 8,8a-octahydro-1-naphthyl] -3,5-dihydroxyheptanoate (prepared as described in Preparation Example 8), except that a method similar to that described in Example la was used. Repeat to give 450 mg of the title compound.

355 mg of allyl 7- [5- (2-thienyl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3-oxo-1, 2, 3, 5, 6, 7, 8 In a similar manner as described in Example 1b, except that 8a-octahydro-1-naphthyl] 3-hydroxy-5oxoheptanoate (prepared as described in Example 8a) is used. Repeated to give 311 mg of the title compound.

630 mg of allyl 7- [5-isoxazol-4-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) 3-oxo-1, 2, 3, 5, 6, 7 , 8, 8a-octahydro-1-naphthyl] -3, 5-dihydroxyheptanoate (prepared as described in Preparation Example 9), except that a method similar to that described in Example la was used. Repeat to give 208 mg of the title compound.

196 mg of allyl 7- [5-isoxazol-4-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) 3-oxo-1, 2, 3, 5, 6, 7 Similar to that described in Example 1b, except that 8, 8a-octahydro-1-naphthyl] -3-hydroxy-5-oxoheptanoate (prepared as described in Example 9a) is used. Repeatedly to give 171 mg of the title compound.

151 mg of 7- [5- (isoxazol-4-yl) methoxyimino-2-2-methyl-8- (2-methylbutyryloxy) -3-oxo in 2.5 ml of a 1: 1 volume mixture of dioxane and water 1, 2, 3, 5, 6, 7, 8, 8a-octahydro-1-naphthyl] -3-hydroxy-5-oxoheptanoic acid (prepared as described in Example 9b) is dissolved. 2.7 ml of 0.1 N aqueous sodium hydroxide solution is then added dropwise to the solution at 0 ° C. over 5 minutes, and the resulting mixture is stirred at room temperature for 1 hour. After stirring, the solution is lyophilized to yield 153 mg of the title compound as a colorless powder that is sensitive to wetting.

843 mg of allyl 7- [5- (5-methylisoxazol-3-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3 oxo-1,2,3,5 , 6, 7, 8, 8a-octahydro-1-naphthyl] -3,5-dihydroxyheptanoate (prepared as described in Preparation Example 10) except that it is described in Example la Repeat in a similar manner to one to yield 310 mg of the title compound.

290 mg of allyl 7- [5- (5-methylisoxazol-3-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3 oxo-1,2,3,5 In Example 1b, except that 6, 7, 8, 8a-octahydro-1-naphthyl] -3 hydroxy-5oxoheptanoate (prepared as described in Example 10a) is used. Repeat in a similar manner as described to give 201 mg of the title compound.

243 mg of allyl 7- [5- (3,5-dimethylisoxazol-4-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3 oxo-1, 2, 3 Example 5 except that 5, 6, 7, 8, 8a-octahydro-1-naphthyl] -3,5-dihydroxyheptanoate (prepared as described in Preparation 11) is used. Repeat in a similar manner as described for yield 95 mg of the title compound.

218 mg of allyl 7- [5- (3,5-dimethylisoxazol-4-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3 oxo-1, 2, 3 , 5, 6, 7, 8, 8a-octahydro-1-naphthyl] -3-hydroxy-5-oxoheptanoate (prepared as described in Example 11a), except that Repeat in a similar manner as described in 1b to afford 155 mg of the title compound.

To 2.7 ml of a 1: 1 volume mixture of dioxane and water 139 mg of 7- [5- (3,5-methylisoxazol-4-yl) methoxyimino-2-2-methyl-8- (2-methylbutyryl Oxy) -3 -oxo-1,2,3,5,6,7,8,8a-octahydro-1-naphthyl] -3hydroxy-5-oxoheptanoic acid (as described in Example 11b) To dissolve). 2.35 ml of 0.1 N aqueous sodium hydroxide solution was then added dropwise to the solution at 0 ° C. over 5 minutes, and the solution was stirred at room temperature for 1 hour. After stirring, the solution is lyophilized to yield 140 mg of the title compound as a colorless powder that is sensitive to wetting.

515 mg of allyl 7- [5- (hexylimino) -2-methyl-8- (2-methylbutyryloxy) -3 oxo-1, 2, 3, 5, 6, 7, 8, 8a-octa 149 mg of the title was repeated in a similar manner as described in Example la, except that hydro-1-naphthyl] -3,5-dihydroxyheptanoate (prepared as described in Preparation 12) was used. Obtain the compound.

140 mg of allyl 7- [5-hexylmethoxyimino-2-methyl-8- (2-methylbutyryloxy) -3-oxo-1,2,3,5,6,7,8,8a-octahydro -L-naphthyl] -3 -hydroxy-5 -oxoheptanoate (prepared as described in Example 12a), except that the title compound is repeated in a similar manner as described in Example 1b. Obtain 106 mg.

11.7 g of benzyl 7- [5- (1,3-dioxane-5-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3-oxo-1, 2, 3, 5, 6, 7, 8, 8a-octahydro-1-naphthyl] -3,5-dihydroxyheptanoate (prepared as described in Preparation Example 13), except that in Example la Repeat in a similar manner as described to give 5.3 g of the title compound.

0.98 g (1.87 mmole) of {2-[5-benzyloxyimino-2 -methyl-8-(2 -methylbutyryloxy) -3 -oxo-1,2 in 20 ml of a 1: 1 volume mixture of dioxane and water , 3, 5, 6, 7, 8, 8a-octahydro-1-naphthyl] ethyl}-4-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2 -one . 19.6 ml of 0.1 N sodium hydroxide solution was then added dropwise to the solution at 0 ° C. over 2.5 hours; Thereafter, the mixture is stirred at the same temperature for 30 minutes, and then further stirred at room temperature for 1 hour. After stirring, the solution is lyophilized. The sodium salt obtained was dissolved in 11 ml of dimethylformamide, then 1.62 ml (18.7 mmole) of allyl bromide was added and the mixture was stirred for 17 hours under a nitrogen atmosphere. After stirring, distillation under reduced pressure removes dimethyl formamide from the reaction mixture. 40 ml of water was added to the residue and the resulting mixture was extracted with ethyl acetate (2 × 30 ml each). The ethyl acetate extract is then washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. The oily residue obtained is purified by silica gel flash column chromatography using a 1: 1 volume mixture of ethyl acetate and hexane as eluent to afford 0.90 g (84% yield) of the title compound.

1.31 g of {2- [5-(furan-2-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3-oxo-1, 2, 3, 5, 6, 7 , 8, 8a-octahydro-1-naphthyl] ethyl}-4-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2 -one in Preparation Example 1, except that A similar method as described is repeated to afford 1.34 g of the title compound.

10.0 g of {2-[5-(1,3-dioxane-5-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3 oxo-1,2,3, 5, 6, 7, 8, 8a-octahydro-1-naphthyl] ethyl}-4-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2 -one except , A method similar to that described in Preparation Example 1 is repeated, to obtain 10.6 g of the title compound.

690 mg of {2-[5-(2-ethoxybenzyloxyimino) -2 -methyl-8-(2-methylbutyryloxy)-3 -oxo-1, 2, 3, 5, 6, 7, 8 , 8a-octahydro-1-naphthyl] ethyl} -4-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one, except that A similar method as described above is repeated to yield 680 mg of the title compound.

970 mg of {2-[5- (2-chlorobenzyloxyimino) -2-methyl-8- (2-methylbutyryloxy) -3-oxo-1, 2, 3, 5, 6, 7, 8, 8a-octahydro-1-naphthyl] ethyl} -4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one as described in Preparation Example 1 except that Similar methods are repeated to afford 970 mg of the title compound.

1.41 g of {2-[5-(2,6-dichlorobenzyloxyimino) -2 -methyl-8-(2-methylbutyryloxy) -3 -oxo-1,2,3,5,6,7 , 8, 8a-octahydro-1-naphthyl] ethyl}-4-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2 -one in Preparation Example 1, except that A similar method as described is repeated to yield 1.33 g of the title compound.

700 mg of {2-[5-(3-methylisoxazol-5-yl) methoxyimino-2 -methyl-8-(2-methylbutyryloxy) -3 -oxo-1,2,3,5 , 6, 7, 8, 8a-octahydro-1-naphthyl] ethyl}-4-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2 -one, except that A method similar to that described in Preparation Example 1 was repeated to yield 736 mg of the title compound.

1.37 g of {2-[5- (2-thienyl) methoxyimino-2 -methyl-8-(2-methylbutyryloxy) -3 -oxo-1,2,3,5,6,7 8, 8a-octahydro-1-naphthyl] ethyl}-4-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2 -one, except that it is described in Preparation Example 1 A method similar to one is repeated to yield 1.28 g of the title compound.

600 mg of {2-[5-(isoxazol-4 -yl) methoxyimino-2 -methyl-8-(2-methylbutyryloxy) -3 -oxo-1,2,3,5,6,7 , 8, 8a-octahydro-1-naphthyl] ethyl}-4-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2 -one in Preparation Example 1, except that A similar method as described is repeated to yield 630 mg of the title compound.

800 mg of {2-[5- (5-methylisoxazol-3-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy)-3 -oxo-1, 2, 3, 5 , 6, 7, 8, 8a-octahydro-1-naphthyl] ethyl}-4-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2 -one, except that A method similar to that described in Preparation Example 1 was repeated to yield 857 mg of the title compound.

1.01 g of {2-[5-(3,5-dimethylisoxazole-4 -yl) methoxyimino-2 -methyl-8-(2-methylbutyryloxy) -3 -oxo-1,2, 3, 5, 6, 7, 8, 8a-octahydro-1-naphthyl] ethyl}-4-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2 -one Except for repeating a similar method as described in Preparation Example 1, 1.02 g of the title compound is obtained.

750 mg of {2-[5-hexylimino-2 -methyl-8-(2-methylbutyryloxy) -3 -oxo-1,2,3,5,6,7,8,8a-octahydro- 1-naphthyl] ethyl} -4 hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one, except for using a similar method as described in Preparation Example 1 563 mg of the title compound are obtained.

To 230 ml of a 1: 1 volume mixture of dioxane and water 10.0 g (18.7 mmole) of {2-[5-(1,3 -dioxane-5 -yl) methoxyimino-2 -methyl-8-(2-methyl) Butyryloxy) -3 -oxo-1,2,3,5,6,7,8,8a-octahydro-1-naphthyl] ethyl} -4-hydroxy-3,4,5,6-tetra Dissolve hydro-2H-pyran-2-one. Thereafter, 196 ml of 0.1 N sodium hydroxide aqueous solution is added dropwise to the solution over 3.5 hours, stirred at 0 ° C for 1 hour, and then further stirred at room temperature for 1 hour. After stirring, the solution is lyophilized. After dissolving the obtained sodium salt in 110 ml of dimethylformamide, 6.67 ml (56.1 mmole) of benzyl bromide was added and the mixture was stirred for 17 hours under a nitrogen atmosphere.

After stirring, distillation under reduced pressure removes dimethylformamide from the reaction mixture. 400 ml of water was added to the residue and the resulting mixture was extracted with ethyl acetate (2 × 300 ml each). The ethyl azetate layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. The oily residue obtained is purified by silica gel flash column chromatography using a 1-2 volume mixture of ethyl acetate and hexane as eluent to afford 11.7 g of the title compound.

43.5 g of N-hydroxyphthalimide is added to 31.1 g of furfuryl chloride solution dissolved in 80 ml of dimethylformamide, and the mixture is cooled to 0 ° C. Thereafter, 40.6 ml of triethylamine is added dropwise to the mixture, and the reaction mixture is stirred at 0 ° C. for 2 hours and then at room temperature for 24 hours. After stirring, the reaction mixture is poured into ice water. The resulting colorless crystals were collected by filtration to give 53.1 g of N-furfuryloxyphthalimide having a melting point of 145 to 147 占 폚.

4.28 g of N-furfuryloxyphthalimide (prepared as described in step (i) above) is dissolved in 20 ml of ethanol and 1.37 g of butylamine are added to the obtained solution. The mixture is then stirred for 1 hour at room temperature and then diethyl ether is added. The mixture is acidified by addition of 10 vol% methanolic solution of hydrogen chloride, and the obtained crystals are collected by filtration to give 2.62 g of the title compound.

A similar procedure as described in Preparation Example 14 (i) was repeated except that 8.10 g of o-chlorobenzyl chloride was used, yielding 7.63 g of N-o-chlorobenzyloxyphthal having a melting point of 161 to 163 ° C. Mid is obtained as colorless crystals.

Thereafter, except that 2.87 g of N-o-chlorobenzyloxyphthalimide (prepared as described in step (i) above) was used, it was carried out in a similar manner as described in Preparation Example 14 (ii) 1.54 g of the title compound having a melting point of 143 to 145 ° C is obtained as colorless crystals.

A similar procedure as described in Preparation Example 14 (i) was repeated except that 9.86 g of 2,6-dichlorobenzyl chloride was used, and 8.31 g of N- (2,6-dichloro having a melting point of 201 to 206 ° C. Benzyloxy) phthalimide is obtained as colorless crystals.

Then, a method similar to that described in Preparation Example 14 (ii), except that 3.22 g of N- (2,6-dichlorobenzyloxy) phthalimide (prepared as described in step (i) above) was used. This yields 2.11 g of the title compound having a melting point of 165-167 ° C as colorless crystals.

To 5.15 g of 5-hydroxymethyl-3 methylisoxazole solution dissolved in 245 ml of tetrahydrofuran are added 8.17 g of N-hydroxyphthalimide and 23.9 g of triphenylphosphine. Then a 13.3 g dimethylazodicarboxylate solution dissolved in 20 ml of tetrahydrofuran is added dropwise to the solution obtained at room temperature under a nitrogen atmosphere. The mixture is then left for 30 minutes, after which the solvent is removed by distillation under reduced pressure. The obtained residue was purified by silica gel flash column chromatography using a 4: 1 volume mixture of hexane and ethyl acetate as eluent to obtain 7.21 g of N- (3-methylisoxazole-5) having a melting point of 129 to 131 占 폚. To obtain methoxyphthalimide.

To a solution of 7.21 g of N-(3-methylisoxazol-5-yl) methoxyphthalimide (prepared as described in step (i) above) dissolved in 80 ml of ethanol was added 2.04 g of butylamine. The mixture is stirred at 60 ° C. for 1 hour. After stirring, the temperature of the reaction mixture is lowered to room temperature, after which the reaction mixture is diluted with 300 ml of diethyl ether and acidified by addition of 10 vol% methanolic solution of hydrogen chloride at 0 ° C. The obtained crystals are collected by filtration to give 3.22 g of the title compound having a melting point of 193 to 198 ° C.

20.3 ml of triethylamine and 9.0 ml of mesyl chloride were added to 8.31 g of 2-thiopanmethanol solution dissolved in 80 ml of ethyl acetate while ice-cooling and stirring, and the mixture was stirred at 0 ° C. for 1 hour and then 3 at room temperature. Stir for more time. Then, the reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is washed in order of 10% w / v aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. The extract is dried over anhydrous sodium sulfate and then the solvent is removed by distillation under reduced pressure to yield 1.39 g of an oily residue. 1.07 g of the oily residue is dissolved in 5 ml of dimethylformamide, and then 0.91 g of N-hydroxyphthalimide is added to the resulting solution. The mixture is cooled to 0 ° C., then 0.85 g of triethylamine is added, and the mixture is stirred at 0 ° C. for 2 hours, then at room temperature for 20 hours, then at 60 ° C. for 1 hour. The reaction mixture is then cooled to room temperature and diluted with water. The aqueous solution is acidified by addition of 10% w / v aqueous hydrochloric acid and the mixture is then extracted with ethyl acetate. The extract is washed in order of 5% aqueous w / v sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The mixture is filtered and then the solvent is removed by distillation under reduced pressure to yield 7.23 g of an oily residue. The oily residue is dissolved in 36 ml of dimethylformamide and 6.14 g of N-hydroxyphthalimide are added to the resulting solution. The mixture is then ice cooled and 5.8 ml of triethylamine is added to the solution. The reaction mixture is stirred for 15 minutes with ice cooling, and then for 17 hours at room temperature. After stirring, the mixture was distilled with water and acidified by addition of 10% w / v aqueous hydrochloric acid; It is then extracted with ethyl acetate. The extract is washed with 5% aqueous w / v potassium carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate and filtered. The solvent is removed from the filtrate by distillation under reduced pressure to yield 9.87 g of N-(2-thiophenmethoxy) phthalimide. All of this compound is dissolved in 75 ml of ethanol and 4.20 ml of butylamine are added to the resulting solution. The mixture is stirred at 60 ° C. for 3 hours. After stirring, the reaction mixture is cooled to room temperature and diluted with diethyl ether. After ice cooling, a 10% methanolic solution of hydrogen chloride is added to acidify. The obtained crystals are collected by filtration to give 5.79 g of the title compound having a melting point of 164 to 167 ° C as colorless crystals.

To 2.00 g of ethyl isoxazole-4 -carboxylate solution dissolved in 20 ml of methylene chloride was added 60 ml of 1.0 M hexane solution of diisobutylaluminum hydride at -78 ° C over 13 minutes. The mixture is then stirred for 5 minutes at the same temperature, then 4 ml of methanol is added and the temperature of the mixture is raised to room temperature.

10 ml of methylene chloride and 3 ml of saturated aqueous sodium chloride solution are added to the reaction mixture, and the mixture is then filtered through a Celite® pad. The filtrate is dried over anhydrous sodium sulfate and then filtered to remove the desiccant. The solvent was removed by distillation under reduced pressure to yield 781 mg of an oily residue, which was purified by distillation using a distillation bulb (120 ° C./7 mmHg) to give 510 mg of 4-hydroxymethylisoxazole.

Melting point is 133-135 DEG C. by carrying out a method similar to that described in Preparation Example 17 (i), except that 505 mg of 4-hydroxymethylisoxazole [prepared as described in step (i)] is used. 621 mg of N-(isoxazol-4-yl) methoxyphthalimide are obtained.

A method similar to that described in Preparation Example 17 (ii) was carried out, except that 597 mg of N- (isoxazol-4-yl) methoxyphthalimide (prepared as described in step (ii) above) was used. To give 338 mg of the title compound.

1.13 g of N- (5-methylisoxazole) was repeated by repeating a method similar to that described in Preparation Example 17 (i) except that 565.6 mg of 3-hydroxymethyl-5-methylisoxazole was used. Yl) methoxyphthalimide is obtained.

Thereafter, 9.27 g of N- (5-methylisoxazol-3-yl) methoxyphthalimide [prepared as described in step (i)] was prepared in a similar manner to that described in Preparation Example 17 (ii). The treatment gives 5.32 g of the title compound having a melting point of 195 to 196 ° C.

A method similar to that described in Production Example 14 (i) was carried out except that 291 mg of 4-chloromethyl-3,5-dimethylisoxazole was used, and 362 mg of N − (having a melting point of 144 to 146 ° C. 3,5-Dimethylisoxazol-4-yl) methoxyphthalimide is obtained.

Melting point was 165 by performing a method similar to that described in Preparation Example 14 (ii) except that 14.8 g of N- (3,5-dimethylisoxazol-4-yl) methoxyphthalimide was used. 8.93 g of the title compound are obtained which is ˜169 ° C.

50 ml of seed culture medium having the above-mentioned composition is charged into a 500 ml Erlenmeyer flask and autoclaved at 120 ° C. for 30 minutes before inoculating microorganisms. A platinum loop from Penicillium citrinum Tom SANK 13380 (Penicillium citrinum Thom SNAK 13380, FERM BP-4129) is transferred to the flask containing the medium aseptically. The inoculated flasks are incubated at 24 ° C. for 3 days on a rotary shaker at 210 rpm.

The 2000 ml Erlenmeyer flask containing 700 ml of seed culture medium is then autoclaved at 120 ° C. for 30 minutes and then inoculated with the entire fermentation broth (about 50 ml) obtained as described above. The flasks were incubated at 24 ° C. for 2 days in a rotary shaker at 210 rpm to prepare a second generation culture.

10% w / v aqueous sodium hydroxide solution is added to adjust the pH to a value of 6.0 to 6.5, after which tap water is added to adjust the total volume to 10 l. The production culture medium 2 is then sterilized by autoclaving at 120 ° C for 30 minutes.

[Supply liquid 4]

Tap water is added to 1600 g of glycerin and 6400 g of Sanmalt S, Sanwa Starch Industry, Ltd. mixture and then the mixture is heated to above 90 ° C. After complete dissolution of the acid malt S, tap water is added to the solution to bring the total volume to 10 l. The solution is then autoclaved at 120 ° C. for 30 minutes.

[Feed liquid B]

600 ml of SanNix PP 2000 (Sanyo Chemical Industries Co., Ltd.) medium is autoclaved at 120 ° C for 30 minutes.

After autoblading, 5 L of production culture medium 1 and 10 L of production culture medium 2 are charged into a 30 1 stainless steel jar fermenter.

The entire contents of the Erlenmeyer flask (approximately 700 ml) containing the second generation cultures prepared as described above are then used only to inoculate the autoclaved production culture medium in the fermentor. The fermentor is incubated at 24 ° C. with agitation at an auto-regulated range of 260-500 rpm, at a pressure of 0.5 kg / cm ² to maintain an air flow of 7.5 L per minute and dissolved oxygen concentration of 3-5 ppm.

For three to six days after the start of inoculation, 150 ml of Feed Liquid B is added to the culture medium once a day (total four times). After the concentration of reducing sugar is 1% or less, feed liquid A is continuously added to keep the pH of the broth at a value of about pH 4.

After 14 days, the resulting broth is harvested.

(2) isolation

The pH of the culture broth (40 L) is added to 800 ml of 6N aqueous sodium hydroxide solution to make 12, and the resulting mixture is stirred at room temperature for 60 minutes. After stirring, the broth is mixed with 1.5 kg of Celite filter aid (Celite filter aid, Celite # 545, trade name manufactured by Johns-Manville Products Corp.) and the mixture is stirred. The resulting mixture is filtered with a filter press to produce a filtrate.

850 ml of 6N aqueous hydrochloric acid solution is carefully added to the filtrate and the pH of the mixture is adjusted to a value of 5.0. 80 L of ethyl acetate is added to the resulting solution and the mixture is stirred to extract the desired product. The organic layer is separated and the aqueous layer is treated with 40 L of ethyl acetate and stirred to extract the desired product. The mixed ethyl acetate extracts are then extracted with 3% w / v aqueous sodium bicarbonate solution 10 1. The aqueous layer is separated and the organic layer is extracted again with 3% w / v aqueous sodium hydrogen carbonate solution.

Carefully add 1600 ml of 6N aqueous hydrochloric acid solution to the mixed aqueous extract and adjust the pH of the mixture to 5.0. 20 L of ethyl acetate is added to the resulting mixture and the mixture is stirred to extract the desired product.

The organic layer is separated and the aqueous layer is treated with 10 L of ethyl acetate and stirred to extract the desired product. The combined ethyl acetate extracts are washed with 15 L of 10% w / v aqueous sodium chloride solution. The extract is then dried over 3000 g of anhydrous sodium sulfate and the solvent is removed by evaporation to dryness under reduced pressure using a rotary evaporator to give an oily residue. The oil residue is dissolved in 1000 ml of ethyl acetate. 0.5 ml of trifluoroacetic acid is added to the solution and the mixture is heated under reflux for 30 minutes in a vessel equipped with a reflux condenser. The contents are cooled to 10 ° C. and then washed twice with 500 ml of 3% w / v aqueous sodium bicarbonate solution and once with 500 ml of 10% w / v aqueous sodium chloride solution. The organic layer is dried over 100 g of anhydrous sodium sulfate and filtered. The filtrate is evaporated to dryness under reduced pressure using a rotary evaporator to separate from the solvent to yield 50 g of an oily residue.

The entire oily residue is dissolved in 500 ml of acetonitrile and the resulting solution is divided into five portions. Each portion was subjected to an ODS reversed phase column [ODS-1050-2OSR, 10 cm (inner diameter) × 50 cm, 15-30 μm (particle size); Kurita Kogyo Co., Ltd.] for chromatography. The column is eluted at a flow rate of 200 m 1 / min using 70% by volume aqueous acetonitrile used as mobile phase. The fraction recovered from the column is monitored by ultraviolet absorption, and fractions having a residence time of 30 to 36 minutes are collected based on the detected peaks.

Purity of the fractions was determined by high performance liquid chromatography (ODS-262, Senshu Kagaku Co., Ltd.) using 70 vol% acetonitrile aqueous solution at 1.0 m1 / min flow rate as mobile phase, monitoring the fractions by ultraviolet absorption at 236 nm. do. Fractions with a residence time of 11 minutes represent a single peak of specific ultraviolet absorption.

The fraction having a residence time of 30 minutes to 36 minutes from reverse phase column chromatography is concentrated by distillation under reduced pressure using a rotary evaporator to distill off acetonitrile. The concentrate is extracted twice with 1/2 of the volume of ethyl acetate. The ethyl acetate extracts are mixed and concentrated by evaporation to dryness under reduced pressure to give 30 g of an oily residue.

The oil is triturated with a mixture of ethanol and water to induce crystallization. 17 g of the title compound are obtained as colorless crystals.

The physicochemical properties of the compound are known and are the same as those described in Japanese Patent Publication No. 56-12114 (= GB Patent No. 1453425) and other documents.

A 500 ml Erlenmeyer flask containing 100 ml of the yeast MY culture medium is inoculated in platinum loops from Amycolate autotrophica SANK 62981 (FERM BP-4105). The flasks are incubated at 28 ° C. on a rotary shaker at 200 rpm.

After 3 days, 20 500 ml Erlenmeyer flasks each containing 100 ml yeast MY culture medium are inoculated respectively into 5 ml flasks containing seed culture. The culture is then incubated with a rotary shaker at 200 rpm. After 2 days, an aqueous solution of sodium salt of ML-236 B is added to the final concentration of 0.1% sodium salt, and the mixture is incubated in a rotary shaker at 200 rpm at 28 ° C. for 5 days.

The fermentation broth is then filtered and the filtrate is absorbed onto 200 ml of nonionic resin, Diaion HP-20 (tradename). The resin is washed with 300 ml of distilled water and the fractions containing the title compound elute with 800 ml of 50% v / v aqueous acetone.

The eluate was concentrated by evaporation to dryness under reduced pressure, and the concentrate was fractionated by ultraviolet absorption at 237 nm by preparative ODS column (ODS-H-5251) chromatography using a 480: 520: 1 volume mixture of acetonitrile, water and acetic acid as eluent. Purify while monitoring. Collect the desired fractions and add their pH to a value of 8.0 by adding aqueous sodium hydroxide solution. The mixture is then concentrated by evaporation under reduced pressure. The concentrate is dissolved in water and the resulting aqueous solution is treated with 50 ml of Diaion HP-20. The resin is washed with 100 ml of distilled water and then eluted with 200 ml of 50% v / v aqueous acetone to give 618 mg of the title compound.

Physicochemical properties are known and are the same as those described in Japanese Patent Laid-Open No. 61-13699 (= GB Patent No. 2077264) and other documents.

Claims (23)

A compound represented by formula (1) and a pharmaceutically acceptable salt and ester thereof: [Formula 1] [Wherein, R represents a hydrogen atom, a methyl group or a hydroxy group; X is carbon number substituted by one or more alkyl groups of 1 to 10 carbon atoms, alkenyl groups of 3 to 10 carbon atoms, cycloalkyl groups of 3 to 10 carbon atoms, aryl groups of 6 to 10 carbon atoms, and carbocyclic aryl groups having 6 to 10 carbon atoms. An aralkyl group having 1 to 6 alkyl groups, or 1 to 3 heterocyclic groups having 5 to 6 ring atoms having a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur heteroatoms, wherein the alkyl and alkenyl groups are unsubstituted Or substituted with one or more substituents A as defined below, wherein the cycloalkyl, aryl, aralkyl and heterocyclic groups are unsubstituted or substituted with one or more substituents B as defined below; A represents a single bond, an alkylene group having 1 to 10 carbon atoms, an alkenylene group having 3 to 10 carbon atoms, an alkynylene group having 3 to 10 carbon atoms, or an alkadieneylene group having 5 to 10 carbon atoms, wherein the alkylene, Alkenylene, alkynylene and alkadienylene groups are unsubstituted or substituted with one or more substituents C as defined below; Y is a heterocyclic group having 5 or 6 ring atoms having a hetero atom selected from the group consisting of an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, and having 1 to 3 nitrogen, oxygen and sulfur hetero atoms; or 1 ˜3 each has a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur hetero atoms and represents a heterocyclic group having 5 or 6 ring atoms bonded to a benzene ring, wherein the aryl, cycloalkyl and heterocyclic groups are unsubstituted or Substituted with one or more substituents D defined; [Substituent A:] Halogen atom, hydroxy group, C1-C4 alkoxy group, C2-C5 aliphatic carboxylic acyloxy group, amino group, carboxyl group and protected carboxyl group; [Substituent B:] Halogen atom, hydroxy group, C1-C4 alkoxy group, C2-C5 aliphatic carboxylic acyloxy group, amino group, carboxyl group, protected carboxyl group, C1-C5 alkyl group, and C1-C5 Haloalkyl group; [Substituent C:] Halogen atom, hydroxyl group, alkoxy group of 1 to 4 carbon atoms, aryloxy group of 6 to 14 carbon atoms, aralkyloxy group, aliphatic carboxylic acyloxy group of 2 to 5 carbon atoms, of 7 to 15 carbon atoms Aromatic carboxylic acyloxy group, an amino group, a C1-C4 alkylamino group, each alkyl group has a C1-C4 dialkylamino group, a C6-C14 arylamino group, and each aryl group has a C6-C14 diaryl Amino group, aralkylamino group, diaralkylamino group, aliphatic carboxylic acylamino group having 2 to 5 carbon atoms, aromatic carboxylic acylamino group having 7 to 15 carbon atoms, carboxyl group and protected carboxyl group, wherein the aryloxy, aralkyloxy The aryl groups of the aromatic carboxylic acyloxy, arylamino, diarylamino, aralkylamino, diaralkylamino and aromatic carboxylic acylamino groups are defined below. Is unsubstituted or substituted with one or more substituents E, wherein the aralkyl moiety for each of the aralkyloxy, aralkylamino and diaralkylamino groups is one to six carbon atoms substituted with one or more aryl groups having 6 to 10 carbon atoms. An alkyl group; [Substituent D] Halogen atom, hydroxyl group, alkoxy group having 1 to 4 carbon atoms, aryloxy group having 6 to 14 carbon atoms, aralkyloxy group, aliphatic carboxylic acyloxy group having 2 to 5 carbon atoms, aromatic having 7 to 15 carbon atoms Carboxylic acyloxy group, mercapto group, alkylthio group having 1 to 4 carbon atoms, arylthio group having 6 to 14 carbon atoms, aralkylthio group, amino group, alkylamino group having 1 to 4 carbon atoms, and each alkyl group having 1 carbon atom A dialkylamino group having 4 to 4 carbon atoms, an arylamino group having 6 to 14 carbon atoms, a arylamino group having 6 to 14 carbon atoms each, an aralkylamino group, a diaralkylamino group and an aliphatic carboxylic acylamino group having 2 to 5 carbon atoms , An aromatic carboxylic acylamino group having 7 to 15 carbon atoms, a nitro group, a cyano group, a carboxyl group, a protected carboxyl group, an alkyl group having 1 to 5 carbon atoms and one to 5 carbon atoms, and one or more substituents defined below. Alkyl groups substituted with group F, wherein the aryloxy, aralkyloxy, aromatic carboxylic acyloxy, arylthio, aralkylthio, arylamino, diarylamino, aralkylamino, diaralkylamino and aromatic car The aryl group of the cyclic acylamino group is unsubstituted or substituted with one or more substituents E as defined below, wherein the aralkyl moiety for each of the aralkyloxy, aralkylthio, aralkylamino and diaralkylamino groups has 6 carbon atoms. An alkyl group having 1 to 6 carbon atoms substituted by one or more aryl groups having ˜10; [Substituent E] Alkyl group having 1 to 4 carbon atoms, hydroxy group, halogen atom, alkoxy group having 1 to 4 carbon atoms, carboxyl group, protected carboxyl group and amino group; [Substituent F] A halogen atom, a hydroxyl group and an aliphatic carboxylic acyloxy group having 2 to 5 carbon atoms. The compound according to claim 1, wherein R represents a hydrogen atom, a methyl group or a hydroxy group; X is C ₁ to C ₁₀ alkyl group, C ₃ to C ₁₀ alkenyl group, C ₃ to C ₁₀ cycloalkyl group, phenyl group, C ₇ to C ₉ aralkyl group or one or two selected from the group consisting of oxygen, sulfur and nitrogen hetero atoms An unsaturated heterocyclic group having 5 or 6 ring atoms, which is a hetero atom, wherein the alkyl and alkenyl group is unsubstituted or substituted with 1 to 4 substituents A ¹ as defined below, and the cycloalkyl, phenyl, aralkyl and heterocyclic groups Is unsubstituted or substituted with 1 to 4 substituents B as defined in claim 1; A represents a single bond, a C ₁ to C ₁₀ alkylene group or a C ₃ to C ₁₀ alkenylene group, a C ₅ to C ₁₀ alkadienylene group or a C ₃ to C ₅ alkynylene group, wherein the alkylene and alkenylene , Alkadienylene and alkynylene groups are unsubstituted or substituted with one or two substituents C ¹ as defined below; Y represents a C ₆ to C ₁₀ aryl group or a C ₃ to C ₈ cycloalkyl group, each of which may be unsubstituted or substituted with one or two substituents D ^{1 as} defined below. [Substituent A ¹ :] Halogen atom and hydroxyl group, C ₁ to C ₄ alkoxy group, C ₂ to C ₅ aliphatic carboxylic acyloxy group, amino group, carboxyl group and protected carboxyl group; [Substituent C ¹ ] A halogen atom, a hydroxyl group, a C ₁ to C ₄ alkoxy group, a C ₆ to C ₁₄ aryloxy group, a C ₂ to C ₅ aliphatic carboxylic acyloxy group, an amino group, and an alkyl group having 1 to 3 carbon atoms 4- and mono- and di-alkyl-substituted amino groups, C ₂ to C ₅ aliphatic carboxylic acylamino groups, C ₇ to C ₁₅ aromatic carboxylic acylamino groups, carboxyl groups and protected carboxyl groups, the above aryloxy groups and aromatic carboxyl groups Ric acylamino group is unsubstituted or substituted with 1 to 3 substituents E ¹ as defined below; [Substituent D ¹ :] Halogen atom, hydroxy group, C ₁ to C ₄ alkoxy group, C ₆ to C ₁₄ aryloxy group, C ₇ to C ₉ aralkyloxy group, C ₂ to C ₅ aliphatic carboxylic acyloxy group , C ₇ to C ₁₅ aromatic carboxylic acyloxy group, mercapto group, C ₁ to C ₄ alkylthio group, amino group, mono- and di-alkyl-substituted amino group having 1 to 4 carbon atoms in each alkyl portion, C ₂ ~ C ₅ aliphatic carboxylic acylamino group, a nitro group, a cyano group, a carboxy group, a protected carboxy group, C ₁ ~ C ₅ alkyl group, C ₁ ~ C ₅ haloalkyl group, C ₁ ~ C ₅ hydroxyalkyl group, and the acyl portion C _An acyloxyalkyl group having ₂ to C ₅ aliphatic carboxylic acyl groups and an alkyl moiety of C ₁ to C ₅ , wherein the aryl groups of the aryloxy, aralkyloxy groups and aromatic carboxylic acyloxy groups are unsubstituted or defined below. 1 to 3 substituents E ¹ are substituted; [Substituent E ¹ ] A compound of the formula ( ¹ ) which is a C ₁ to C ₄ alkyl group, a hydroxy group, a halogen, a C ₁ to C ₄ alkoxy group, a carboxyl group, a protected carboxyl group and an amino group, and a pharmaceutically acceptable salt and ester thereof. A compound according to claim 1, wherein R represents a hydrogen atom, a methyl group or a hydroxy group; X is a C ₁ to C ₁₀ alkyl group, a C ₃ to C ₁₀ alkenyl group, a C ₃ to C ₁₀ cycloalkyl group, a phenyl group, a C ₇ to C ₉ aralkyl group or one or two of the group consisting of oxygen, sulfur and nitrogen hetero atoms An unsaturated heterocyclic group having 5 or 6 ring atoms, which is a selected hetero atom, wherein the alkyl and alkenyl group is unsubstituted or substituted with 1 to 4 substituents A ¹ as defined below, wherein the cycloalkyl, phenyl, aralkyl and hetero The ventilation is unsubstituted or substituted with 1 to 4 substituents B as defined in claim 1; A is a C ₁ to C ₁₀ alkylene group, a C ₃ to C ₁₀ alkenylene group, a C ₅ to C ₁₀ alkadienylene group or a C ₃ to C ₅ alkynylene group, and the alkylene, alkenylene, alkadienylene and alkoxy The nylene group is unsubstituted or substituted with one or two substituents C ¹ as defined below; Y is a heterocyclic group having 5 or 6 ring atoms where 1 to 3 are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur heteroatoms or heteroatoms selected from the group consisting of 1 to 3 nitrogen, oxygen and sulfur heteroatoms, benzene A heterocyclic group having 5 or 6 ring atoms bonded to the ring, wherein the heterocyclic group is unsubstituted or substituted with 1 or 2 substituents D ¹ as defined below; [Substituent A ¹ ] A halogen atom, a hydroxy group, a C ₁ to C ₄ alkoxy group, a C ₂ to C ₅ aliphatic carboxylic acyloxy group, an amino group, a carboxy group and a protected carboxy group; [Substituent C ¹ ] Halogen atom, hydroxy, C ₁ to C ₄ alkoxy group, C ₆ to C ₁₄ aryloxy group, C ₂ to C ₅ aliphatic carboxylic acyloxy group, amino group, carbon number of each alkyl part 1 Mono- and di-alkyl-substituted amino groups having 4 to 4, C ₂ to C ₅ aliphatic carboxylic acylamino groups, C ₇ to C ₁₅ aromatic carboxylic acylamino groups, carboxyl groups and protected carboxyl groups, acyloxy groups and aromatics The aryl group of the carboxylic acylamino group is unsubstituted or substituted with 1 to 3 substituents E ¹ as defined below; [Substituent D ¹ ] A halogen atom, a hydroxyl group, a C ₁ to C ₄ alkoxy group, a C ₆ to C ₁₄ aryloxy group, a C ₇ to C ₉ aralkyloxy group, a C ₂ to C ₅ aliphatic carboxylic acyloxy group, C ₇ to C ₁₅ aromatic carboxylic acyloxy group, mercapto group, C ₁ to C ₄ alkylthio group, amino group, mono- and di-alkyl-substituted amino group having 1 to 4 carbon atoms in each alkyl portion, C ₂ ~ C ₅ aliphatic carboxylic acylamino group, a nitro group, a cyano group, a carboxy group, a protected carboxy group, C ₁ ~ C ₅ alkyl group, C ₁ ~ C ₅ haloalkyl group, C ₁ ~ C ₅ hydroxyalkyl group, and the acyl portion C ₂ An acyloxyalkyl group having a C ₅ aliphatic carboxylic acyl group and an alkyl moiety of C ₁ to C ₅ , wherein the aryl groups of the aryloxy, aralkyloxy and aromatic carboxylic acyloxy groups are unsubstituted or defined below. Is substituted with three substituents E ¹ ; [Substituent E ¹ ] A compound of the formula ( ¹ ) which is a C ₁ to C ₄ alkyl group, a hydroxy group, a halogen, a C ₁ to C ₄ alkoxy group, a carboxyl group, a protected carboxyl group and an amino group, and a pharmaceutically acceptable salt and ester thereof. The compound according to claim 1, wherein R represents a hydrogen atom, a methyl group or a hydroxy group; X is C ₁ to C ₁₀ alkyl group, C ₃ to C ₁₀ alkenyl group, C ₃ to C ₁₀ cycloalkyl group, phenyl group, C ₇ to C ₉ aralkyl group or one or two selected from the group consisting of oxygen, sulfur and nitrogen hetero atoms Unsaturated heterocyclic groups having 5 or 6 ring atoms, which are hetero atoms, wherein the alkyl and alkenyl groups are unsubstituted or substituted with 1 to 4 substituents A ¹ as defined below, wherein the cycloalkyl, phenyl, aralkyl and The heterocyclic group is unsubstituted or substituted with 1 to 4 substituents B as defined in claim 1; A is C ₁ ~ C ₁₀ alkylene group, C ₃ ~ C ₁₀ alkenylene group, C ₅ ~ on C ₁₀ alkadi a carbonyl group or a C ₃ ~ C ₁₀ alkynylene group, the alkenylene group, the alkadi alkenylene and alkynylene groups Unsubstituted or substituted with one or two substituents C ¹ as defined below; Y is a hydrogen atom; [Substituent A ¹ ] A halogen atom, a hydroxy group, a C ₁ to C ₄ alkoxy group, a C ₂ to C ₅ aliphatic carboxylic acyloxy group, an amino group, a carboxy group and a protected carboxy group; [Substituent C ¹ ] Halogen atom, hydroxy group, C ₁ to C ₄ alkoxy group, C ₆ to C ₁₄ aryloxy group, C ₂ to C ₅ aliphatic carboxylic acyloxy group, amino group, carbon number of each alkyl part 1 Mono- and di-alkyl-substituted amino groups having 4 to 4, C ₂ to C ₅ aliphatic carboxylic acylamino groups, C ₇ to C ₁₅ aromatic carboxylic acylamino groups, carboxyl groups and protected carboxyl groups, aryloxy groups and aromatics The aryl group of the carboxylic acylamino group is unsubstituted or substituted with 1 to 3 substituents E ¹ as defined below; [Substituent D ¹ ] A halogen atom, a hydroxyl group, a C ₁ to C ₄ alkoxy group, a C ₆ to C ₁₄ aryloxy group, a C ₇ to C ₉ aralkyloxy group, a C ₂ to C ₅ aliphatic carboxylic acyloxy group, C ₇ to C ₁₅ aromatic carboxylic acyloxy group, mercapto group, C ₁ to C ₄ alkylthio group, amino group, mono- and di-alkyl-substituted amino group having 1 to 4 carbon atoms in each alkyl portion, C ₂ ~ C ₅ aliphatic carboxylic acylamino group, a nitro group, a cyano group, a carboxy group, a protected carboxy group, C ₁ ~ C ₅ alkyl group, C ₁ ~ C ₅ haloalkyl group, C ₁ ~ C ₅ hydroxyalkyl group, and the acyl portion C ₂ An acyloxyalkyl group having a C ₅ aliphatic carboxylic acyl group and an alkyl moiety of C ₁ to C ₅ , wherein the aryl groups of the aryloxy, aralkyloxy and aromatic carboxylic acyloxy groups are unsubstituted or defined below. Is substituted with three substituents E ¹ ; [Substituent E ¹ ] A compound of formula 1 which is a C ₁ to C ₄ alkyl group, hydroxy, halogen, a C ₁ to C ₄ alkoxy group, a carboxyl group, a protected carboxyl group and an amino group, and a pharmaceutically acceptable salt and ester thereof. A compound according to claim 1, wherein R is a hydrogen atom, a methyl group or a hydroxy group; X is a C ₁ to C ₁₀ alkyl group, C ₃ to C ₁₀ alkenyl group or C ₃ to C ₇ cycloalkyl group, wherein the alkyl and alkenyl group is unsubstituted or substituted with one or two substituents A ² as defined below, The cycloalkyl group is unsubstituted or substituted with one or two substituents B ¹ as defined below; A is a single bond, a C ₁ to C ₅ alkylene group C ₃ to C ₅ alkenylene group, C ₅ to C ₈ alkadienylene group, wherein the alkylene, alkenylene and alkadienylene group are unsubstituted or defined below Or substituted with two substituents C ² ; Y is a C ₆ to C ₁₀ aryl group or a C ₅ to C ₇ cycloalkyl group, which may be unsubstituted or substituted with one or two substituted D ² as defined below. [Substituent A ² ] Halogen atom, hydroxyl group, C ₂ to C ₅ aliphatic carboxylic acyloxy group, carboxyl group and protected carboxyl group; [Substituent group B ^1] halogen atom, hydroxy, C ₁ ~ C ₄ alkoxy group, C ₂ ~ C ₅ aliphatic carboxylic acyloxy groups, C ₁ ~ C ₅ alkyl group and C ₁ ~ C ₅ haloalkyl group; [Substituent C ² ] A halogen atom, a hydroxyl group, a C ₁ to C ₄ alkoxy group, an amino group, a mono- and di-alkyl-substituted amino group having 1 to 4 carbon atoms in each alkyl portion, and a C ₂ to C ₅ aliphatic carboxylic acyl Amino group and [substituent D ² ] a halogen atom, a hydroxy group, a C ₁ to C ₄ alkoxy group, a C ₆ to C ₁₄ aryloxy group, a C ₇ to C ₉ aralkyloxy group, an amino group, and an alkyl group having 1 to 4 carbon atoms Phosphorus mono- and di-alkyl-substituted amino groups, C ₂ to C ₅ aliphatic carboxylic acylamino groups, nitro groups, cyano groups, carboxyl groups, protected carboxyl groups, C ₁ to C ₅ alkyl groups, C ₁ to C ₅ haloalkyl groups, C ₁ to C ₅ hydroxyalkyl group, and acyloxy alkyl group in which the acyl moiety is a C ₂ to C ₅ aliphatic carboxylic acyl group and the alkyl moiety is C ₁ to C ₅ , wherein the aryloxy, aralkyloxy and aromatic carboxylic acyl The aryl group of oxy group is unsubstituted or defined below 1 to 3 Substituent is replaced by E ^1; [Substituent E ¹ ] A compound of the formula ( ¹ ) which is a C ₁ to C ₄ alkyl group, a hydroxy group, a halogen, a C ₁ to C ₄ alkoxy group, a carboxyl group, a protected carboxyl group and an amino group, and a pharmaceutically acceptable salt and ester thereof. A compound according to claim 1, wherein R is a hydrogen atom, a methyl group or a hydroxy group; X is a C ₁ to C ₁₀ alkyl group, C ₃ to C ₁₀ alkenyl group or C ₃ to C ₇ cycloalkyl group, wherein the alkyl and alkenyl group is unsubstituted or substituted with one or two substituents A ² as defined below, The cycloalkyl group is unsubstituted or substituted with one or two substituents B ¹ as defined below; A is a C ₁ to C ₅ alkylene group, a C ₃ to C ₅ alkenylene group or a C ₅ to C ₈ alkadienylene group, wherein the alkylene, alkenylene and alkadienylene groups are unsubstituted or defined below Substituted with one or two substituents C ² ; Y is a heterocyclic group having 5 or 6 ring atoms where 1 or 2 are heteroatoms selected from the group consisting of nitrogen and oxygen heteroatoms, or 5 ring atoms having 1 or 2 heteroatoms selected from the group consisting of nitrogen and oxygen heteroatoms Or said heterocyclic group having 6 and bonded to the benzene ring is unsubstituted or substituted with one or two substituents D ² as defined below; [Substituent A ² ] Halogen atom, hydroxyl group, C ₂ -C ₅ aliphatic carboxylic acyloxy group, carboxyl group and protected carboxyl group; [Substituent group B ^1] halogen atom, hydroxy, C ₁ ~ C ₄ alkoxy group, C ₂ ~ C ₅ aliphatic carboxylic acyloxy groups, C ₁ ~ C ₅ alkyl group and C ₁ ~ C ₅ haloalkyl group; Substituent C ^{2 A} halogen atom, a hydroxyl group, a C ₁ to C ₄ alkoxy group, an amino group, a mono- and di-alkyl-substituted amino group having 1 to 4 carbon atoms in each alkyl portion, and a C ₂ to C ₅ aliphatic carboxylic acyl Amino group; And [substituent D ² ] a halogen atom, a hydroxy group, a C ₁ to C ₄ alkoxy group, a C ₆ to C ₁₄ aryloxy group, a C ₇ to C ₉ aralkyloxy group, an amino group, and an alkyl group having 1 to 4 carbon atoms Mono- and di-alkyl-substituted amino groups, C ₂ to C ₅ aliphatic carboxylic acylamino groups, nitro groups, cyano groups, carboxyl groups, protected carboxyl groups, C ₁ to C ₅ alkyl groups, C ₁ to C ₅ haloalkyl groups, C _An acyloxyalkyl group having ₁ to C ₅ hydroxyalkyl group and an acyl moiety C ₂ to C ₅ aliphatic carboxylic acyl group and an alkyl part C ₁ to C ₅ , wherein the aryloxy, aralkyloxy and aromatic carboxylic acyl The aryl group of the time is unsubstituted or substituted with 1 to 3 substituents E ¹ as defined below; [Substituent E ¹ ] A compound of the formula ( ¹ ) which is a C ₁ to C ₄ alkyl group, a hydroxy, a halogen, a C ₁ to C ₄ alkoxy group, a carboxyl group, a protected carboxyl group and an amino group, and a pharmaceutically acceptable salt and ester thereof. A compound according to claim 1, wherein R is a hydrogen atom, a methyl group or a hydroxy group; X is a C ₁ to C ₁₀ alkyl group, C ₃ to C ₁₀ alkenyl group or C ₃ to C ₇ cycloalkyl group, wherein the alkyl and alkenyl group is unsubstituted or substituted with one or two substituents A ² as defined below, The cycloalkyl group is unsubstituted or substituted with one or two substituents B ¹ as defined below; A is a C ₁ to C ₁₀ alkylene group, a C ₃ to C ₁₀ alkenylene group or a C ₅ to C ₁₀ alkadienylene group, wherein the alkenylene and alkadienylene group is unsubstituted or one or two substituents defined below Substituted with C ² ; Y represents a hydrogen atom; [Substituent A ² ] Halogen atom, hydroxyl group, C ₂ to C ₅ aliphatic carboxylic acyloxy group, carboxyl group and protected carboxyl group; [Substituent B ¹ ] A halogen atom, a hydroxyl group, a C ₁ to C ₄ alkoxy group, a C ₂ to C ₅ aliphatic carboxylic acyloxy group, a C ₁ to C ₅ alkyl group and a C ₁ to C ₅ haloalkyl group; Substituent C ² Halogen atom, hydroxy group, C ₁ to C ₄ alkoxy group, amino group, mono- and di-alkyl-substituted amino group having 1 to 4 carbon atoms in each alkyl moiety and C ₂ to C ₅ aliphatic carboxylic acyl A compound of formula 1 which is an amino group, and a pharmaceutically acceptable salt ester thereof. A compound according to claim 1, wherein R represents a hydrogen atom; X is a C ₁ to C ₇ alkyl group, a C ₃ to C ₅ alkenyl group or a C ₃ to C ₇ cycloalkyl group, wherein the alkyl and alkenyl group is unsubstituted or substituted with one or two substituents A ³ as defined below, The cycloalkyl group is unsubstituted or substituted with one or more substituents B ² as defined below; A is a single bond, a C ₁ to C ₅ alkylene group or a C ₃ to C ₅ alkenylene group, which may each be unsubstituted or substituted with one or two substituents C ³ as defined below; Y represents a C ₆ to C ₁₀ aryl group or a C ₅ to C ₇ cycloalkyl group, which may be unsubstituted or substituted with one or two substituents D ³ , respectively, defined below; [Substituent A ³ ] Halogen atom and carboxy group; [Substituent B ² ] A halogen atom and a C ₁ to C ₅ haloalkyl group; [Substituent C ³ ] A hydroxy group and a C ₁ to C ₄ alkoxy group; Substituent D ^{3 A} halogen atom, a hydroxyl group, a C ₁ to C ₄ alkoxy group, an amino group, a mono- and di-alkyl-substituted amino group having 1 to 4 carbon atoms in each alkyl moiety, C ₂ to C ₅ aliphatic carboxylic acyl A compound of formula (1) which is an amino group, a nitro group, a C ₁ to C ₅ alkyl group, a C ₁ to C ₅ haloalkyl group and a C ₁ to C ₅ hydroxyalkyl group, and a pharmaceutically acceptable salt and ester thereof. A compound according to claim 1, wherein R represents a hydrogen atom; X is a C ₁ to C ₇ alkyl group, a C ₃ to C ₅ alkenyl group or a C ₃ to C ₇ cycloalkyl group, wherein the alkyl and alkenyl group is unsubstituted or substituted with one or two substituents A ³ as defined below, The cycloalkyl group is unsubstituted or substituted with one or more substituents B ² as defined below; A is a C ₁ -C ₅ alkylene group or a C ₃ -C ₅ alkenylene group, which can be unsubstituted or substituted with one or two substituents C ³ , respectively, defined below; Y is a heterocyclic group having 5 or 6 ring atoms wherein 1 or 2 are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur heteroatoms, which may be unsubstituted or substituted with 1 or 2 venting D ³ as defined below. have ; [Substituent A ³ ] Halogen atom and carboxy group; [Substituent B ² ] A halogen atom and a C ₁ to C ₅ haloalkyl group; [Substituent C ³ ] A hydroxy group and a C ₁ to C ₄ alkoxy group; Substituent D ^{3 A} halogen atom, a hydroxyl group, a C ₁ to C ₄ alkoxy group, an amino group, a mono- and di-alkyl-substituted amino group having 1 to 4 carbon atoms in each alkyl moiety, C ₂ to C ₅ aliphatic carboxylic acyl A compound of formula (1) which is an amino group, a nitro group, a C ₁ to C ₅ alkyl group, a C ₁ to C ₅ haloalkyl group and a C ₁ to C ₅ hydroxyalkyl group, and a pharmaceutically acceptable salt and ester thereof. A compound according to claim 1, wherein R represents a hydrogen atom; X is a C ₁ to C ₇ alkyl group, a C ₃ to C ₆ alkenyl group or a C ₃ to C ₇ cycloalkyl group, wherein the alkyl and alkenyl group is unsubstituted or substituted with one or two substituents A ³ as defined below, The cycloalkyl group is unsubstituted or substituted with one or more substituents B ² as defined below, A is a C ₁ to C ₁₀ alkylene group, or a C ₃ to C ₇ alkenylene group or a C ₅ to C ₈ alkadieneylene group, which are Each may be unsubstituted or substituted with one or two substituents C ³ as defined below; [Substituent A ³ ] Halogen atom and carboxy group; [Substituent B ² ] A halogen atom and a C ₁ to C ₅ haloalkyl group; And [substituent C ³ ] hydroxy group and a C ₁ to C ₄ alkoxy group; Y is a hydrogen atom and a pharmaceutically acceptable salt and ester thereof. The compound of claim 1, wherein R is a hydrogen atom; X is C ₁ ~ C ₇ alkyl group; A is C ₁ ~ C ₅ alkylene group and; Y is a C ₆ to C ₁₀ aryl group or a C ₅ to C ₇ cycloalkyl group, which are unsubstituted or substituted with one or two substituents D ⁴ as defined below; Substituent D ⁴ A compound of the formula (1) which is a halogen atom, a hydroxy group, a C ₁ to C ₄ alkoxy group and a C ₁ to C ₅ alkyl group, and a pharmaceutically acceptable salt and ester thereof. A compound according to claim 1, wherein R is a hydrogen atom; X is C ₁ ~ C ₇ alkyl group; A is C ₁ ~ C ₅ alkylene group and; Y is a C ₆ to C ₁₀ aryl group which is unsubstituted or substituted with one or two substituents D ⁵ as defined below; [Substituent D ⁵ ] A compound of formula (1) which is a halogen atom and a C ₁ to C ₄ alkoxy group, pharmaceutically acceptable salts and esters thereof. A compound according to claim 1, wherein R is a hydrogen atom; X is C ₁ ~ C ₇ alkyl group; A is C ₁ ~ C ₅ alkylene group and; Y represents a heterocyclic group having 5 or 6 ring atoms wherein 1 or 2 are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur heteroatoms, which are substituted or unsubstituted with 1 or 2 substituents selected from alkyl groups having 1 to 5 carbon atoms Compounds of formula (1) which may be substituted, and pharmaceutically acceptable salts and esters thereof. The compound of claim 1, wherein R is a hydrogen atom; X is C ₁ ~ C ₇ alkyl group; A represents an alkylene group of C ₁ ~ C _10; Y is a hydrogen atom and a pharmaceutically acceptable salt and ester thereof. 7- [5-benzyloxyimino-2-methyl-8- (2-methylbutyryloxy) -3-oxo-1,2,3,5,6,7,8,8a-octahydro-1-naph Yl] -3 hydroxy-5 oxoheptanoic acid and pharmaceutically acceptable salts and esters thereof. 7- [5- (1,3-dioxane-5-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3-oxo-1,2,3,5,6, 7, 8, 8a-octahydro-1-naphthyl]-3-hydroxy-5-oxoheptanoic acid and pharmaceutically acceptable salts and esters thereof. 7- [5- (2-thienyl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3-oxo- 1, 2, 3, 5, 6, 7, 8, 8a- Octahydro-1 naphthyl] 3-hydroxy-5 oxoheptanoic acid and pharmaceutically acceptable salts and esters thereof. 7- [5- (isoxazole-4-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3-oxo-1,2,3,5,6,7,8, 8a-octahydro-1naphthyl] 3-hydroxy-5oxoheptanoic acid and pharmaceutically acceptable salts and esters thereof. 7- [5- (5-methylisoxazol-3-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3-oxo-1,2,3,5,6, 7, 8, 8a-octahydro-1-naphthyl]-3-hydroxy-5-oxoheptanoic acid and pharmaceutically acceptable salts and esters thereof. 7- [5- (3-methylisoxazole-5-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3-oxo-1,2,3,5,6, 7, 8, 8a-octahydro-1-naphthyl]-3-hydroxy-5-oxoheptanoic acid and pharmaceutically acceptable salts and esters thereof. 7- [5- (3,5-dimethylisoxazol-4-yl) methoxyimino-2-methyl-8- (2-methylbutyryloxy) -3-oxo-1,2,3,5, 6, 7, 8, 8a-octahydro-1-naphthyl 1-3-hydroxy-5 oxoheptanoic acid and pharmaceutically acceptable salts and esters thereof. 22. An active compound for inhibiting cholesterol biosynthesis containing at least one compound of formula (1) or a pharmaceutically acceptable salt or ester thereof claimed in any one of claims 1 to 21, and a pharmaceutically acceptable carrier or diluent are mixed. Pharmaceutical composition, characterized in that. An effective amount of an active compound that inhibits cholesterol biosynthesis containing at least one compound of formula (1) or a pharmaceutically acceptable salt or ester thereof claimed in any one of claims 1 to 21 may be used for a disease caused by blood cholesterol imbalance. A method of treatment administered to a mammal other than a human suffering from. [Formula 2] Wherein X, Y, R and A are as defined in claim 1 and R ^a represents an alkyl, alkenyl or aralkyl group. [Formula 3] [Wherein X, Y, R, R ^a and A are as defined in claim 1. The compound of Formula 2 is oxidized to obtain a compound of Formula 3, and the compound of Formula 3 is de-esterified to obtain a compound of Formula 1, and the compound of Formula 3 or Formula 1 A process for preparing a compound of formula (1) as claimed in any one of claims 1 to 21, or a pharmaceutically acceptable salt or ester thereof, comprising the step of converting to an ester or salt thereof.